Introduction

COVID-19 pandemic spread in almost all, all over the globe countries .Millions have been affected and millions died. The situation necessitate international efforts of medical internists epidemiologists, immunologist, and vaccine technologist .Four main preventive vaccine versions were becoming in hand for human mass vaccination within one year after the pandemic spread. So far concerning immunology of the disease. Scientists early in the pandemic starts to assess humoral immunity suitable for sero-diagnosis and sero-therapy of the disease as well as tempting and still tempting to developing the COVID-19 valid preventive vaccines. Currently, cell and lymphocyte immunologists take the forefront position in COVID-19 research. They articulate cellular immunology, flow cytometery, single cell RNA sequencing, mass transcriptomics, proteomics and cell-cell inter- actomics for tracing lymphocyte immunotypes and the allied cell type interactions .As well as their roles in; the pathogenesis, immune- pathogenesis, and disease outcome prediction.

Aiming

The objective of the present special issue “IMMUNE CELLS  IN COVID-19” published in IJPC was focusing onto the; ontogeny, biology, molecular biology, immuno-typing of immune cells and their roles in covuid-19.In which the latest information were collected, analyzed and formatted as series of opinion papers.

Scope

Lymphoid, lympho-myeloid and myeloid cell lineages for lymphocytes, monocytes and granulocytes as well as their mature forms are forming the backbone of human and mammalian immune system. The function of the immune system is mainly to recognize and destroy foreign invaders via a tripartite responses as; innate, immune cross-roads and adaptive immune responses. Immune cells the subject of the present special issue were assigned to these three immune system arms.

List of Contents

Section One: Innate Immunity

1. Immunology of mononuclear phagocytes system in pulmonary patho-type of COVID-19.*

Section Two: Immune Cross-roads

1. The interplay of NKT cells in severe sars-cov-2 human infections*
2. TH17 cells and the intercellular functions in severe, critical, deceased and vaccine of COVID-19*

Section Three: Adaptive Immunity

1. B Cell immunology of COVID-19*.
2. Regulatory Lymphocytes in COVID-19*.
3. 6-MAIT functions in homeostasis,covid-19 infected an covid-19

*The authorship;

IBRAHIM MS SHNAWA, College of Biotechnology, University of Qasim and Hilla University, College Babylon, Iraq.

Abstract

Mononuclear Phagocyte System MPS has an essential role in all stages of human SARS-COV-2 pulmonary infections. The objective of the present opinion paper was to through a light on the forefront achievements on the immunology of MPS in COVID-19. Single cell mRNA sequencing, single nucleus RNA sequencing, PCR, transcriptomics, flow cytometery, histo and gross pathology were the main assays tempted for assessments through an in-vitro, ex-vivo and in-vivo experimental settings. Monocyte, macrophage, alveolar macrophage, dendritic cells via an increment or decrement shift in number or function could probe the disease severity. MPS cells are either primer infected and lead to serial cellular events ended with severity. Or the epithelial cells found in the micro-environmental continuum with the APS were infected leading to MPS cell infection followed by cell-cell cross-talks, positive loop feedback mechanisms with T lymphocyte and/or MPS cells interferon axis functions. The overall immune response patterns of the lung in severe COVID-19 were; hyper-inflammation, immune impairment, hypoxia and severity terminated with death if not managed at earliest. An immune six point severity index was proposed as a diagnostic battery to be of use in an advance immunology laboratory was suggested. Molecular immune concept of circuit was briefed. MPS immune functions in pulmonary COVID-19 hold the position of double sward beneficial in some functional aspects and deleterious in others.

Keywords

Alveolar, Asymptomatic, Cytometery, Dendritic cell, Flow, Infection, Macrophages, Monocyte

Introduction

Mononuclear phagocyte system MPS take part in the functions of the human immune system both in health and disease. As a system is composed of circulating monocyte and tissue resident forms, the tissue resident forms got different names in different tissue microenvironment as; Glial in brain, alveolar in lungs, Kupffer in liver, osteoclast in bone, dendritic in spleen and other lymph glands and blood stream and Langerhans in skin. Some of which undergoes phase transition as that of glial cells in central nervous system. MPS performed immune functions both in the natural (innate) and adaptive immune responses. In other word they take part in immune cross-roads functions. In general MPS interplay immune functions in viral diseases and have special immune potentials in COVID-19. In health, MPS performed; phagocytosis, antigen presentation, shaping the adaptive immune responses, production of cytokines  and chemokines. While in disease state MPS played a role in the infectious inflammatory processes and in immune tissue  injuries due to an excessive cytokine production insitue in the affected tissue microenvironment [1-3]. In the present opinion tempts were made  to review the immunology of mononuclear phagocyte cell system in pulmonary COVID-19.

Cellular Immunology of MPS

MPS cells originated from the pluripotent stem cells in bone marrow in human adults. From the stem cells, lympho-myeloid progenitor cell line was developed which then differentiated to pro- monoblast, mono-blast, pro-monocyte then to monocyte in blood stream. From blood stream migrate to tissue compartments. During such migration they undergo morphologic and functional changes that fits to the target tissue compartment or organ while migration within blood vessels would not accompanied by morphologic, functional and/or mitogenic changes.

MPS cells are of large sizes and have multiple secondary lysozymes. They are characterized  by  active  endoplasmic reticulum and active Golgi apparatus which means  have  both  active biosynthetic pathways and active secretions with an evident acclimatization to their microenvironment. In lungs MPS express oxidative metabolism, their half-life were ranged between 60 to90 days in various organ/systems. During the inflammatory stimuli, therein  there  are  increments  in  the  in  their  development   in bone marrow and disseminated to various tissues through blood stream. On surface of MPCS cells there are numbers of markers   like:  MHCI,  MHCII,  C1,  C2,  FC,  CD11,  CD18,  CD13,   CD16,

CD17, CD31, and IA. The biophysical characteristics of MPS are; stimulated by bacterial lipo-polysachaaride LPS and mitogenic lectins, adhere to glass, recognize the antigens by TLR receptor. They secrete; hydrolytic enzymes, enzyme  inhibitors,  cytokines,  fat derived factors, complement components, and mirobicidal materials. When activated lymphocyte produce both of; macrophage inhibitory factor MIF it affects inhibition in spread of macrophages and   macrophage   stimulating   factors   which   stimulate   them for pinocytosis, phagocytosis, and induce the appearance of immune associated antigen Ia and assist in antigen presentation. MPS own specialized mechanisms for recognition of different inflammatory stimuli. If the stimulus is microbe, they will evolve number of killing mechanisms. They evolve three highly efficient recognition and clearing mechanisms of immune complexes through phagocytosis. The presence of MPS in continuum of  inflammatory  responses  they indicated either sub-acute or chronic inflammatory state. MPS cells act as; second line defender of human and mammalian body, antigen processing, antigen presentation, cytokine production and recognition of inflammatory responses [1-3].

Cell Molecular Immunology

There are varieties of natural immune protein that have the ability to recognize and detect human infection. These proteins are either soluble or structural entities like; soluble lysosome, complement components or complement receptors. The recognition process is through pattern recognition on the surface of the microbes. Among these receptors are the Toll-like receptor, the TLRs which are proteins of collectin nature that have the ability to recognize certain molecular patterns on the microbial surface. Such recognition molecules are forming strong features of natural (innate) immunity. TLRs are considered as a part of normal immune physiology. In the structural sense TLRs are forming a family of trans-membrane proteins that belongs to a class of animal lectins known as collectin proteins. TLR family is composed of more than ten different receptors. Most of the human and mammalian body tissues express at least one type of TLR. Though all TLRs are expressed onto; macrophages, dendritic cells, mast cells and B cells. TLRs interplayed an array of immune functions like; microbial sensors, cell signaling activators, enhancers for the expression of both; inflammatory and immune response genes, cross- linking of pattern-recognition molecules on the surface of microbe with TLRs act as danger signal to increase the microbicidal activity of phagocytic macrophages and allow them to activate T cells. TLRs made an important link between innate and adaptive immune responses. On TLRs activation, macrophage co-stimulatory molecules will converts macrophage phagocytes into antigen presenting macrophages which able to activate T cells [4-7].

Immunology of MPS in Human Virus Infections

The invading mammalian and human viruses when gain foot- hold in their respective hosts. They are recognized via their surface pattern recognition molecules PRM by the surface TLRs of MPS in blood stream and tissue resident. PRM cross-linked TLRs then virus pinocytosed, or through macro-pinocytosis and/or receptor mediated endocytosis in to the cell interior, Nikitina et al. [2018] the cross-link lead to transform of pinocytosed cell into antigen presenting cells. The processed virus peptides conjugated with MHC molecule and migrate out on the surface of MPS. The antigen presenting MPS will either activate naïve T cell to be Th2 triggering naïve b lymphocytes to grow, proliferate and expand as an effector antibody producing and memory B cells. Or activate naïve T cells to Th1 cells triggering T cells to be effector CD8+ cytotoxic T cells, CD4 T cells and memory T cells. The burden of virus load can be eradicated by the action of cytotoxic T cells or neutralized by the antiviral antibody and/or cleared by the direct action of interferons. The presence of molecular mimicking viral epitope with host tissue cells may initiate through the action of autoantibodies or auto-reactive cells immune tissue injuries terminated by autoimmune diseases. Excessive cytokine production by T cells or MPS also lead to inflammatory and immune responses with consequences of immune tissue injuries. The possible occurrence of viral immunosuppressive epitopes will trigger a state of infectious immunosuppressive conditions [6-9].

Immunology of MPS in SARS-COV-2 Infections

The circulating and tissue resident MPS cells, the monocyte and tissue macrophages participate in all stages of SARS-COV-2 human infection. They contribute to: (i) innate immune reactions (ii) shaping adaptive immune reactions, (iii) comorbidity predisposing to clinical infections, (iv) virus resistance, (v) virus dissemination, (vi) the host factors that determine disease severity, (vii) induction of immune tissue injury, (viii) recovery and (ix) sequalae (Table 1) [10-13].

Table 1: Immune cell deviations in human COVID-19 lungs

Immuno-Inflammatory Responses

Severe SARS-COV-2 infection induce haemo-phagocytic syndrome due to the infiltration of pro-inflammatory monocytes, a rare condition expressed as an over excerbant inflammatory response due to development of hyper-cytokinemia together with depletion of the adaptive immune compartment which may explain the appearance of sepsis in many severe COVID-19 cases Gomez-Rail [23]. Macrophage activation syndrome MAS is a condition of systemic hyper- inflammation and often be noted in infection and malfunctioning. It is typified by marked up-regulated expression of pro-inflammatory cytokines. This sort of strong inflammation results in severe tissue injury. Macrophage within MAS state produce high amount of pro- inflammatory cytokine upon stimulation.  Inflammation  is  known to destruct the balance between coagulation and fibrionolysis [14]. The inflammatory cytokines TNFalpha and IL1 instruct macrophage and monocytes to produce tissue factor TF. TF activate coagulation while IL1 anIL6 increase the production of plasmalogin activation inhibitor. Hence, overproduction of inflammatory cytokines along with MAS also promotes intravascular coagulation Otsuka and Senio [15]. Dys-regulated inflammatory syndrome DIS. DIS is generated by mononuclear phagocytes (a rich source of pro-inflammatory cytokines) upon encounter of the virus within the tissue continuum via two stage activation mechanisms which is not specific to the initiating virus. This is relevant to the case of SARS-COV-2 virus infection were age and predisposing comorbidities enhances the risk of severe outcome due to DIS [11].

Human severe SARS-COV-2 pulmonary infection leads to inflammation and tissue destruction with a consequence of an immune mediated fibrosis which remains even in to convalescent phase. In a group of severe pulmonary infected patients with COVID-19. IA aided CT scan were used to score fibrosis via fibrosis index IF. Twelve patients with severe COVID-19 were investigated for IF, they were sub-grouped into IFlo and IF hi. Mononuclear cell were collected from those patients and investigated by single cell RNA sequencing, IF hi group have shown low mononuclear phagocytic cell, low IFN gene profiling as compared to that of IFlo subgroup   of patients. Mononuclear phagocyte could probe the prognosis of immune mediated ling fibrosis [16-21].

Monocyte Responses

In an in-vivo study setting SARS-COV-2 infection sensed by monocyte and macrophages, such sensation forms the inflammosomes that activate caspase I and gasdermin D leading to inflammatory cell death, the pyroptosis and release of potent inflammatory mediators. About 6% of blood monocyte of COVID-19 patients are infected with SARS-COV-2 virus. This virus infection of monocyte depends on the uptake of antibody-opsoinzed virus by FC gamma receptors. The internalized virus begins to replicate within the infected monocyte but infection is aborted and the infectious virus was not detected in the culture supernatant of the infected monocyte. Instead the infected monocyte undergoes pyroptosis mediated by activation of NLRP3 and AIM2 inflammosomes, caspase I and gasdermin D. In same culture settings, the addition of the COVID-19 vaccinee plasma does not promote AB dependent monocyte infection. Moreover tissue resident macrophages but not the infected epithelium and endothelium from lung autopsies from the deceased patients with COVID-19 have activated inflammosomes. The overall of findings suggest that ab-dependent SARS-COV-2 uptake by monocytes and macrophages triggers inflammatory cell death that abort the products of the infectious virus but cause systemic inflammation [14]. Though there was a report discounts the possibility of infection of both lymphocyte and monocytes [22,23].

Among the manifestation of SARS-COV-2 infection in man is the high systemic inflammation and immune dys-regulation. To obtains a mechanistic insight. An ex-vivo cell culture setting in which epithelial cells were co-cultured with monocytes and B cells. Epithelial cells were infected with SARS-COV-2 virus during the incubation period infected epithelial cells interacted with monocyte and B lymphocyte. Strong responses were induced both in monocyte and B cells with SARS-COV-2 inflammatory gene clusters which reproduce immune cell deviation. Similar to that deviation noted in the blood and lung myeloid cells from COVID-19 patients. Earliest infection of epithelial cells with SARS-COV-2 virus triggers inflammatory malformation of COVID-19 patients leading to raise of virus specific monocyte inflammatory phenotypes Leon et al. [24].

In a series of moderate COVID-19 patients, peripheral blood monocyte were investigated, the infection triggers inflammatory responses that stimulate an interferon stimulated gene driven phenotypes, cellular dysfunction epitomized by loss of HLADR receptor expression and induction of alarmin expression is documented in their features in severe cases. Pulmonary macrophages in COVID-19 were derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in determintal loop of pro- inflammatory cytokine release and recruitment of cytotoxic effector cells, thereby, exacerbating tissue damage in the site of infection [25].

Alveolar Macrophage Responses

In an experimental setting, two deceased severe COVID-19 patients were subjected within few hours to an anatomical and pathological study. Mucous plugs were found in all respiratory tracts, terminal bronchioles and pulmonary alveoli. Autopsy samples were processed and tissue samples were collected, sectioned and stained then examined. Real time PCR was performed to detect SARS- COV-2 Viral RNA. Flow cytometeric analysis was done to detect the direct binding of S protein and expression ofACE2 receptors on the macrophage surface. It was evident an extensive impairment of type I alveolar epithelial cells and atypical hyperplasia in type II alveolar epithelium with formation of halyn membrane, focal hemorrhage, exudation, pulmonary edema and consolidation. The mucous plug with fibrous exudates in alveoli together with alveolar macrophage dysfunction was the characteristic abnormalities. The SARS-COV-2 infection was detected in; alveolar epithelium, alveolar macrophages and hilum associated lymphoid tissue. SARS-COV-2 spike proteins interact with and bind ACE2 receptors. Infection of alveolar macrophages might derives cytokine storm [21].

SARS-COV-2 alveolitis were mapped in a human clinical setting in which broncho-alveolar lavage fluid samples were collected from within 48 of intubation from 86 severe COVID patients needing ventilation. In the  majority  of  these  patients  the  alveolar  space  is persistently enriched with alveolar macrophages and T cells without neutrophils. Single cell RNA sequencing was done to five  of the broncho-alveolar lavage fluids. Besides bulk and single cell transcriptomic profiling were suggesting that SARS-COV-2 infect alveolar macrophages, the infected alveolar macrophages in turn respond by recruiting T cells. These T cells release interferon gamma that triggers alveolar macrophages to secrete inflammatory cytokines and further promte T cell recruitments. Findings suggested that SARS- COV-2 causes slowly infecting, specifically-limited alveolitis in which aveolar macrophages incubating virus transcripts and T cells form positive feedback loop that derives progressive alveolar inflammation. Thus, SARS-COV-2 infected alveolar macrophages forms positive feedback loop with T cells in severe COVID-19 disease [20].

Tempts were made to investigate host responses at the level of lung tissue using single nucleus sequencing of 116000 nuclei from lungs of COVID-19 deceased in individuals and underwent rapid autopsies along with seven control individuals. Integrated analysis identified alterations in cellular compositions, transcriptional cell state and cell-cell interactions. The lungs from COVID patients were highly inflamed with dense infiltrates of aberrantly activated monocytes- derived macrophages and alveolar macrophages but had impaired T cell responses. Monocyte/macrophage derives interleukine 1B and epithelial cell derived IL6 were the unique features of COVID lung infection as compared to other viral pneumonias. Alveolar type II cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition to into alveolar type I cells resulting in imparted lung regeneration with expansion of pathologic fibroblasts accounting for the rapidly ensuing pulmonary fibrosis in COVID-19 [19,26].

Dendritic Cells Responses

In a study on a series of convalescent COVID-19 patients peripheral blood mononuclear phagocyte cell were investigated in an in-vitro settings. Early infectious events of SARS-COV-2 with MPS has shown; impaired type I interferon responses, elevated inflammatory cytokine and chemokine levels. The virus even in absence of productive replication in the plasmocytoid DC mediate vigrous TLR7/TLR8 dependent production of both interferon type I and III and inflammatory cytokine as well as chemokine known to contribute to a state of hyper-cytokinemia’ Cytokine Storm”. Which were released from these DC in an ACE2 independent but Neuropilin-1 dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PDL-1 marker, a feature of type I IFN producing cells. In comparison hospitalized COVID-19 patients displayed low frequency of circulating pDC with inflammatory phenotype. Early interaction of SARS-COV-2 and immune cells  occurring  invitro and proved ex-vivo indicate the role of pDC-interferon axis regulate antiviral state in asymptomatic and severe COVID-19 patients. Such findings may indicate crucial and protective role of pDC/IFN I axis in COVID-19 patients [18].

In an in-vivo experimental settings tackling moderate to severe COVID-19 patients. These patients were subjected to high dimensional flow cytometery focusing on MPS cells. It was evident that there were redistribution of monocyte subsets towards intermediate monocyte and general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocyte-myeloid-derived cell suppressor-like cells and high frequency of pre- DC2. Such MPS cell phenotypic alteration and their precursors were cell lineage specific and associated with either the general response to infection of COVID-19 severity. This included an interferon- imprint DCs observed in all patients and a decreased expression of co-inhibitory molecules CD200R in pDcs, DC2 and DC3 subsets in the severely sick patients. Such findings stands as a prove for the MPS dys-regulation associated with severe COVID-19 patients [17].

DCs recognize viral infections and trigger innate as well as adaptive immune responses. COVID-19 severity is highly influenced by the host immune responses and modulation of DCs generation and functions. After the establishment of SARS-COV-2 infection, DCs could play an important role in the immunopathology of the disease. In a series of 65 COVID-19 patients covering mild, moderate to severe infection forms were subjected to analysis of DC circulating populations. Results of such analysis has shown long lasting reduction in DC subpopulation with an expression of functionally impaired – HLADR+ cells lacking DC markers. A higher CD163+ CD14+ cells among DCs subpopulations correlate with systemic inflammation. Depletion and functional impairment of DCs beyond the acute phase play a role in inflammatory responses of COVID-19 patients [16].

Circuit

In the molecular immune sense circuit means a communication form between two immune cells living with in one tissue continuum. In which one cell activated by an inducer, infection will produce mediator, cytokine that activate the other immune cell to produce other mediator, cytokine which in turn affect the first immune cell to produce other mediator. In severe COVID-19 pneumonia infection of alveolar macrophage lead them to produce T cell chemo-attractants. These T cells produce interferon gamma to induce inflammatory cytokine release from the alveolar macrophages and further promote T cell activation. Thus Alveolar macrophages containing the virus and T cells form a positive feedback loop that derives persistent alveolar inflammation [20,25]

Six Points Severity Index

Since studies performed on severe COVID-19 patients were from different nations and different geographical regions across the globe. As well as the sampling and techniques tempted were somewhat different. Thus to hypothetical suggestions for a COVID-19 severity index, one should hold four assumptions as; (i) The sense of severity is of relative homogeneity (ii) Different MPS cells have equal opportunity to face local or systemic viral loads (iii) The function of the MPS cell functions are of similar state and (iv) The invented index components are of equal weights in the evaluation consideration;

1. Low counts of DCs subpopulations in the peripheral blood stream, impaired function and loss of surface.
2. DCs-interferon axis function stand as an index of severity and viral persistence.
3. Low count of broncho-alveolar macrophages and poor transition of type II to type I epithelial cells parallels with severity.
4. Alveolar Macrophage-alveolar T cell are set on parallel with severity.
5. Epithelial prior infection pave the way for alveolar macrophage and B cell infectious activation.
6. Deceased COVID-19 patients associated with alveolar macrophage infection consequences, the pyroptosis and sepsis.

Conclusions

During clinical human SARS-COV-2 pulmonary infection forms, mononuclear phagocyte system cells and epithelial cells are prone to this virus infection. The infection of APS cells is of antibody dependent type. On APS cell infection virus replication cause molecular alterations in; cellular composition, cellular transcription state, and cell-cell interactions. Secretory protein exports in these infected cells are amplified leading to the production of pro-inflammatory and inflammatory cytokine. At the whole cellular levels infected APS cells undergoes immune deviations like; lack of cell surface markers, appearance of intermediate phenotypes, suppressor phenotypes, inhibitory marker bearing phenotypes as well as reduction in numbers in the peripheral blood stream. Reduction in numbers of APS cells  as well as alveolar epithelial cell phase transition impairments were implicated with immune mediated pathological pulmonary fibrosis. Alveolar epithelial cell infection may triggers alveolar macrophage infection and B lymphocytes. Alveolar macrophage infection initiates bilateral positive feedback mechanisms with T lymphocytes. DC cells undergo long lasting reduction in numbers, functional impairments and lack of surface markers. DC functions together with interferons in an axis form leading to regulation of antiviral state in asymptomatic and severe cases. APS cell infections initiate haemo-macrophage syndrome, macrophage activation syndrome, and intravascular coagulation, implicated in immune mediated pulmonary fibrosis, pyroptosis, and terminated by sepsis.

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Abstract

Natural Killer T lymphocytes [NKT cells] share the characteristics of innate and adaptive immune cells. Though their immune cell identity is still a matter of debate among lymphocyte immunologists. Currently, NKT cells are of three subsets as; NKT type I, NKT type II and NKT like cells. NKT type I is quite filling this cell definition. Three immune phenomena are evident concerning NKT interplay with viral infected human host as; immune evasion, immuno-pathogenesis, and immune protection. Immuno-pathogenesis and immune protection appeared to be operable in COVID-19 disease. The present opinion paper was aimed at briefing the role interplayed by NKT cells in severe SARS-COV-2 human infections. Host response showed reduced circulating total NKT cells, but some NKT immune subtypes may express an increment shifts in this severe infection form. The biology of NKT cells in severe SARS-COV-2 infections own an array of immune features as; immune-metabolic dysfunction, mitochondrial dysfunction, marked expression of apoptotic and inhibitory receptor genes and ramified in to six immune subtypes.

Keywords

Evasion, Immune, Inhibitory, Metabolism, Pathogenesis, Protection, Receptors and SARS-COV-2

Introduction

Human lymphocytes are of several immune-types as; B, T, NK and NKT. The efforts of scientists concerning the immunology of NKT cells appeared to be little as compared to other lymphocyte immune-types. NKT as an immune-type and definition is a matter  of debates among lymphocyte immunologists. Recently, evident published efforts concerning NKT cells. They share characteristics of both innate and adaptive immune functions. NKT can be immune- pathogenic and/or immune-protective depending  on  the  intensity of the tissue micro-environmental stimuli during human microbial infections. Some human pathogenic viruses displayed an immune mediated evasion mechanism against NKT cells both in function  and in count limiting. The present opinion was aimed at briefing the interplay of NKT in human severe SARS-COV-2 infection [1-5].

NKT Cell Biology

Ontogeny

Lymphoid cell progenitor migrates from bone marrow to thymus. Arrival of these progenitors to the thymic micro-environment insults these cells to undergo positive and negative selection procedures. These selection procedures mediated by variety of cytokines cell surface molecule, signal transducers, transcription factors and other regulatory factors. A key step in NKT maturation is their acquisition of innate effector function mediated by pro-myelocytic leukemia zinc finger PLZF. Another key step is the acquisition of cytokine secretion ability in which an adoption of constitutional expression of cytokine gene transcripts. Such cytokine gene transcripts need intra-thymic signaling through GM-CSF in order to become competent cytokine secretors. VDJ recombination via stochastic events leads to generation of invariant TCR. Acquisition of NKT phenotype appear to be driven by invariant TCR CD1d. Positive selection of NKT needs interaction of invariant TCR on immature NKT expressing both CD4 and CD8 with CD1d expressed on cortical thymocyte themselves. Both alpha galactosyl Cer NKT agnosts and DCs overexpressing CD1d played critical role in NKT thymic negative selection [4].

Identity

NKT cells are defined as lymphocyte expressing CD3+CD56+ surface receptors [6,7]. Lipid antigen reactive CD1d restricted  T cells most of which do not express CD56 [8]. Koay et al. [9] were formulating important NKT defining criteria as; (i) CD56+ T cells do not equate NKT cells, (ii) CD56+ T cells are heterogeneous T cells but not NKT cells and (iii) The use of CD56 T cells in predicating COVID-19 outcomes needs more validation. Khan and Khan [3] mentioned three subsets of NKT of which only NKTtype I with Koay et al. [9] defining criteria as in Table 1 as well as six subtypes, Table 2.

Table 1: NKT CELL subsets*

Table 2: NKT subtypes*

NKT Cell Molecular Biology

NKT cells  recognize  lipid  stimulating  antigens  through  CDR3 alpha and CDR3 loops. These complementary determining regions are the hyper-variable regions of TCR that complement an antigen shape. Crystallographic and biophysical analysis of alpha galactosylceramide (alpha GalCer) recognition by human CD-1d resistant TCR that utilize a V alpha 3-1-J alpha 18 re-arranged and displays more restored specificity of alpha linked glycolipid than iNKT TCRs. TCR alpha and CDR2 alpha loops have frequent divergence. This TCR employs convergence recognition strategy to engage CD-1d (Alpha Galcer) with binding affinity approximate 2um almost identical to that of an iNKT [10,11]. The hydrophilic groups of the lipoidal antigen contribute relatively little to CD-1d groove and the top of the alpha helcies are involved in lipid antigen presentation which suggest a conventional mode of presentation and recognition. NKT differentiation has unique management for their differentiation which is highly lympha-toxin dependent [12].

NKT Cellular Evasion

Pathogenic human viruses adopt number of strategies for evasion of both innate and adaptive arms of immune responses in human host. HIV weakens the immune system functions by depleting the numbers of CD4 T cells [13]. HIV-1 reduces the expression ofCD-1d molecules by increasing internalization and retains them in the trans- Golgi network. The down regulation in cell surface CD-1d is caused by interaction with in the continuum of intra-cytoplasmic tyrosine with HIV-1 NEF protein, leading to an early NKT depletion in HIV-1 infected individuals. West-Nile virus interferes with the interaction of DCs with NKT cells with net result of pro-inflammatory cytokine secretion [3].

NKT Cellular Immunobiology

T lymphocytes are of many subsets among which the NKT cells that have common surface markers and functional characteristics with both conventional T lymphocyte and natural killer cells. Major NKT cells express semi-invariant T cell receptor TCR that reacts with glycolipid antigens presented by major histocompatibility complex class I related protein CD-1d on the surface of antigen presenting cells APC. Both infectious and inflammatory conditions do activate NKT to be rapidly producing immune-modulatory cytokines. NKT may influence the function and the activation state of other immune cells [4]. The NKT semi-invariant alpha Beta TCRs recognize mammalian glycol-sphigo-lipid and microbial alpha glycuranylceramides found on the cell wall LPS of gram negative bacteria. This dipartite recognition of the auto and microbial ligands underlies innate-like antimicrobial functions mediated by CD40L induction, massive helper TH1, TH2 cytokines and release of chemokines. NKT and DCs performed a sort of reciprocal activation NKT can regulate a range of immunopathologic condition through unknown mechanisms. NKT legends holds a position between innate and adaptive immunity serving as a model system for structural biology of glycolipid trafficking and recognition [14]. NKT lymphocyte tissue distribution is unusual, they are found in large numbers in liver and lymph nodes but to a lesser extent La Jolla Institute of Immunology [15]. NKT served as an important regulator of the immune responses [16].

NKT Immune Functions

NKT cells are able to substantial cross-talk with other innate and adaptive immune cells. NKT when activated with alpha-GalCer, the activation will lead to rapid cytokine production of both Th1 and TH2 cytokines and chemokines though other NKT subsets when activated produce IL17 cytokine. The mode of cytokine activation of NKT cell starts rapid early in activation events, then late in the activation process the production ceased. NKT can mediate immune protection against a wide range of pathogens including bacteria viruses, fungi and parasites. In an experimental laboratory animal settings NKT mediate immune protection against low dose pathogenic challenge. Though in high dose challenge can induce hyper-cytokinemia terminated by sepsis [4].

NKT in Virus Disease

NKT Cells have anti-viral potentials against hepatitis B virus [17], herpes simplex virus-1, lymphocytic chorio-meningitis virus and influenza A virus [18]. They constitute an important arm of the innate immune responses against pathogenic viruses and can regulate adaptive immune responses through modulation of the antigen presenting cells. NKT exerts direct cytolytic effects and retards viral replication [3].

NKT in SARS-COV-2 Infections

A show case analysis of four series of severe SARS-COV-2 infection in different parts of the world is performed by four different research teams. The analysis covered number of patients, age/sex, clinical samples, and nature of the cellular investigations. At most single cell RNA sequencing, transcriptomic analysis and flow cytometery. The tracked immune cell types were NKT, NK, and T cells. As the SARS- COV-2 infection progressed NKT cells reduced with an apparent immune-metabolic dys-regulation, cellular dysfunction as well as mitochondrial dys-regulation (Table 3) [7,10,19,20]. Among these four studies Yang et al. [10] presented a novel detailed investigation on the role of NKT in SARS-COV-2 severe infection and be briefed in the following paragraph.

Table 3: NKT interplay in severe and mild sars-cov-2 human infections

In a clinical setting in to which COVID-19 series of patients and controls were subjected to single cell RNA sequencing in order to determine lymphocyte and mononuclear cell profiles. The number  of patients and subjects were; mild 24, moderate, severe 36, critical, died 13, mild recovered 79, severe recovered 50.  Fifty  patients were tested by single cell RNA sequencing. There was evident that decrease in percentages of lymphocyte in patients is associated with severity. The lymphocyte profiles in PBMC were found that CD8+ T, MAITs, gamma delta T cell, Mono DCs and pDCs decrease significantly as disease progress. While the percentages of plasma   B CD94+, monocytes and platelets increased significantly. The NKT cell percentages in severe COVID-19 decreased significantly as the disease progressed and in convalescent. TM3 expression in NKT cells of 202 COVID patients and controls were grouped into six cell subtypes. Increased Tm3 expression in NKT associated with NKT depletion in severe SARS-COV-2 infections [10]. In the followings  a deduction of features of NKT in COVID-19 from Yang et al. [10] study;

• High levels of expression of CD147CD26
• High expression of Tim3 promotes NKT depletion and dysfunction.
• Decrease in circulating NKT counts as the disease
• High expression of apoptotic and mitochondrial
• Tim3NKT has capacity to secret IFNgamma, IL4 and
• Expression of co-stimulatory inhibitory receptors PD-L, CTL4 and

Conclusions

Lymphocyte profile studies of SARS-COV-2 infection forms have shown variable picture of increase in one immune-type and decrease in others. Generally speaking, lymphogenesis increased as the disease progressed. T, NK, and NKT were affected to a variable degree. Total NKT count in circulation decreased as the disease progressed. Though there are some subtypes of NKT cells increased as the disease progressed.

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Abstract

TH17 cells displayed multiple immune functions in viral human infections including SARS-COV-2. The objective of the present opinion paper was to deduce the actual contribution of these cells in various infection phases of SARS-COV-2 in man. The deduction tempts to: (i) map the immune-typing of TH17 cells in: severe, critical, deceased and Vaccinee via show case analysis and (ii) suggest the pathogenic mechanism of TH17 cells in this disease. The show case analysis of five research papers  published  between  2020  and  2022  indicated  that:  TH17  cells  are  of  two  main  subsets,  the  nonpathogenic and the pathogenic was with, marked plasticity, pleomorphism and instability. On the onset of the clinical infection through hospital admission the patient peripheral blood has shown twice TH17 counts than in normal controls. In uncontrolled progressed COVID-19, the TH17 cell count drop in peripheral blood and enriched in lungs with marked elevation in counts and clonal expansion therein in severe critical and deceased cases. Critical cases on recovery showed TH17 cell counts restoration to normal. Peripheral blood Th17 cells inhibit Teg while in lung both of TH17 and T reg counts were elevated. TH17 cell recruit neutrophils during the infection progress and interacts with various subsets of macrophages and DCs with an outcome of hypercytokinemia and tissue pathology. Based on these facts, the opinion suggested: (i) TH17 as predictor of severity, critical and deceased as well as (ii) the possibleTH17 cells pathogenic mechanisms operable in cases of SARS-COV-2 human disease.

Keywords

Cell, Clonal, COVID-19, Expansion, Pathogenic, TH17

Introduction

TH17 cells are heterogeneous distinct lineage of CD4+ T cells. They are differentiated from naïve T cells through the action of cytokine micro-environmental stimuli. TH17 are basically of two subsets the nonpathogenic and the pathogenic [1]. These helper cells take part in extra-cellular bacterial infections, yeast infections, viral infections including SARS-COV-2 and auto-immune diseases. TH17 performed dual immune functions: the immune-pathogenic and to lesser extent the immune-protective [1-6]. The objective of the present opinion paper was to: (i) map the role of TH17 through the show case analysis of five immune-typing studies of TH17 cells and (ii) suggest the pathogenic mechanisms of these cells in COVID-19, during the period of 2020 till 2022.

Show Case Analysis Approaches

To assess the current holdings of the scientific workers in immunology of SARS-COV-2 infections in man, a sum of 150 current published works through the period of 2020 till 2022 were allocated. These efforts were analyzed so far concerning the CD4+ T cell subsets in COVID-19. Among which ten were concern the role of TH17 in this disease. Of the ten, one was proving TH17 role indirectly from cytokine profiles, five adopted flow cytometery, single cell mRNA sequencing and immunoinformatic approaches to the immune cells recovered from peripheral blood and broncho-alveolar leavage. The rest four review articles were already depending on flow cytometery proving that TH17 cells in association with severe COVID-19 disease and considered as supplementary to this work. The adopted five research works (Table 1) were the raw materials for the show case analysis to deduce the role of TH17 in various phases of human COVID-19 disease [1-12].

Table 1: The show case analysis test research articles

TH17 Cells

Basic TH17 Cell Biology

TH17 cells are distinct lineage of CD4+ T cells that differentiated from naïve T cells, secret the cytokines IL17 A and IL17f and express the lineage specific transcription factor RORC. Both of TH17 and TH17/Th1 clones showed selective expression of IL23R and CCR6 in addition to RORC. Th17 help B cells, express low cytotoxicity and low susceptibility to action of autologous T reg. and critical in clearance of extracellular microbial pathogens [14]. They are of two subsets pathogenic and nonpathogenic [1] (Table 2). These helper cells are pleomorphic, instable and exhibit a sort of plasticity. The TH17/TH1 subset can revert to Th1 cells. Hence some workers denote them as heterogenic helper cells [1,14].

Table 2: Th17 cell subset characteristics

TH17 Cell Differentiation

T helper lymphocytes featured by the expression of CD4+ T cells surface markers are the central cell subset of adaptive immunity. CD4 T cells can recognize proteins of microbial pathogens by their unique surface TCR. TCR can shape antigens and organize against them. Both of the TCR-antigen recognition and the signal of TCR engagement integrated stimuli initiate sort of transcriptional changes that guide naïve T cells towards a specialized function. These stimuli include cytokine, soluble mediators or bacterial products in the microenvironment. This differentiation process needs the regulatory interplay of specific intracellular signal transducer and activator STAT protein in the process. STAT eventually induces the dominant transcription factor TF. TF represent the master lineage specific factor. TF controls the transcriptional program of the cell covering: cytokine production and chemokine receptor expression that mediate trafficking to various organs: this network helps each T cell subsets to exert their specific functions in response to antigens available in the assigned tissue. The T cell TF is a T-Box protein in TH1, GATA b binding protein in TH2, and retinoic acid related orphan receptor gamma-t RORCg-t in TH17 and fork head box3 in T regs [16-19]. Any insult of what so ever nature to this differentiation mechanisms lead to dys-regulation mechanism in various steps of the T cell growth, maturation and response to challenge. Such dysregulation can contribute to pathological responses just as in case of immune mediated diseases. For TH1 and TH17 cells and allergenic responses for TH2. The fate decision of the naïve T cells is largely affected by the cytokine surrounding environment. The Th17 differentiation process encoded by the expression of two effector genes: IL17a and IL17f together with multiple player processes are involved in the different stages of differentiation. The STAT, RORC-g-t axis, RORA, Ahr IPF4 and BATF markers set the initial chromatin accessibility that allows the transcriptional programs. Among which the RO RCg-t is determinative for the expression of IL17a and IL17f genes.

Two different cytokine cocktails lead to two different TH17 subsets. TGFB and IL6 induce nonpathogenic TH17 cells characterized by the co-expression of IL10. While IL6 and IL23 but not TGFB lead  to differentiation of the pathogenic TH17 cells. Both of the subsets would express RORCg-t but the pathogenic subset of TH17 cells are more plastic, polymorphic and have tendency for transition towards TH1 cells. For any naïve T cell differentiation, the concentration and the gradient of TGFB is crucial, high concentration induces T regs associated genes. While restraining T bet and TH1 genes possibly inhibit TH17 pathogenic responses. There is a developmental overlap between TH17, Th1 and T regs. Such overlap might be caused by the complex cytokine dynamics [1,2,20-22].

TH17 Cell and Cellular Interactions

TH17 cells are known to inhibit T reg. responses in peripheral blood of COVID-19 patients [7]. They can induce the neutrophil  and epithelial responses provided by the presence of environmental microbial insults [2]. Within the continuum of COVID-19 pneumonic lungs, TH17 cells interact with pro-inflammatory, pro-fibrotic macrophages, DCs and pDCs [9].

TH17 Cell Immune Functions

TH17 cells performed dual immune function in immune- pathogenesis of viral infections and/or immune protection [6]. They are involved in neutrophil and epithelial cell immune response to extracellular microbes and the initiation of autoimmune diseases [2]. Th17 cell may interplay with the pathogenicity of allergy, asthma and human inflammatory diseases [14].

TH17 Cells in Viral Infections

TH17/IL17 hinders and limits viral infections via several mechanisms as: Enhancing  TH1  responses,  promoting  cytotoxic  T cell activity, modulating antiviral B cell responses and inducing protective inflammatory responses. They may limit the viral induced organ pathology, inhibiting inflammation and mediating protective immune responses. Th17 cells/IL17 cytokine may promote viral infection through different mechanisms as: Antagonizing antiviral TH1, T regs and CTL responses, enhancing survival of infected cells, promoting viral intracellular replication, take part in evolution of tissue pathology and fibrosis [6].

TH17 Cells in Various Phases of SARS-COV-2 Human Infection

The TH17 cells were confirmed both in peripheral blood and lung compartments of various phases of COVID-19, Tables 3-6. Early acute infection and on admission to hospital, TH17 cells were of twice count than that of asymptomatic and controls. T regs were reduced in count and function [1]. On progress under un-controlled conditions, severe state, TH17 counts were reduced in circulation. Both TH17 cells and T regs were increased with clonal expansion in lung compartment in severe COVID-19. In critical or deceased cases both TH17 and T regs were amplified in counts and expansion. But on recovery from severe or critical states TH17 and T reg counts were restored to normal. In line with Th17 count elevation these cases there were reduction in CD4+ T cells, Cd8+ T cells both in circulation and lung compartment. TH17 suppress the T regs and triggers neutrophils causing recruitment to the affected tissue compartment and interacts with each of pro-inflammatory, and pro-fibrotic macrophages, DCs, pDCs, and monocytes. Such intercellular interactions may terminated by an overt inflammatory cytokine production leading to a state of hyper-cytolinemia, the cytokine storm [9]. Th17 cell clone expansions in lung compartment were higher than that in circulation. Lung resident TH17 cell clones can be either merely resident or of mixed resident and migratory forms from circulation. Other T cell subsets were showing various degrees of clonal expansion [9].

Table 3: Circulatory TH17 cells in severe and vaccine of COVID-19 as evident in the three show case analyzed groups

Table 4: Circulatory and pulmonary Th17 cells severe, critical, deceased and vaccine of COVID-19 as evident in the two show case analyzed groups

Table 5: Circulatory Th17 cells severe, critical, critical deceased and vaccine COVID-19 as evident in the five show case analyzed groups

Table 6: Pulmonary existed TH17 cells in various forms of COVID-19 as evident in two show case analyzed groups in comparison to gut Th17 in Chron’s disease

TH17 Cell Suggested Pathogenic Mechanisms

Since TH17 cells expressed low cytotoxicity, though to be a pathogenic helper cell it should express other supportive means to make it able to perform its pathogenic influences. Hence, this opinion paper tempted to hypothesize theoretical suggested mechanisms operable in induction of immune tissue injuries in the lung compartments. They can be coined as follows:

• TH17 cells when interacts with pro-inflammatory macrophages and inflammatory macrophages, they will induce excessive inflammatory cytokines forming cytokine storm mediating tissue pathology consequences of COVID-19 [9].
• Th17 cells recruits neutrophils to lung compartment whereby the affected tissue niche, therein neutrophils produce excessive inflammatory cytokines and reactive O2 intermediates mediating immune tissue injury [9].
• On inhibition of T reg by TH17 cells, they lend the cellular microenvironment allowance of up regulation of auto-reactive T cells to initiate autoimmune pathologic tissue injury [7,10].
• The TH17 cell interaction with pro-fibrotic macrophages may initiate lung tissue fibrotic lesions, the known consequences of COVID-19 pneumonia [9].
• TH17/Th1 cells are known to be: plastic, pleomorphic and instable they my undergoes transition to TH1 cells producing IFNG cytokines and other inflammatory cytokines leading to hyper inflammation in lung paranechyma the sign of COVID-19 pneumonic lungs [15].

Conclusions

TH17 cells associated with the pathogenesis of COVID-19. Circulatory TH17 subset is distinct from lung tissue resident TH17 cell subset. The tissue resident TH17 cells are expanded as tissue specific subset, as mixed clones of migratory and tissue resident TH17 cell clones. On clinical onset of the disease they were of twice count level than controls and inhibit T regs. But in progression during uncontrolled affection, Th17 cell and T reg cells gaining higher counts and marked clonal expansion therein lung compartments as compared to peripheral blood both in severe and critical cases. Though they both reduced to variable degrees in circulation, on recovery of severe and critical cases TH17/T reg ratios restored to normal.

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