scholarly journals The role of unconventional T cells in COVID-19

2021 ◽  
Author(s):  
Kristen Orumaa ◽  
Margaret R. Dunne
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Protective Role ◽  
T Cell Subsets ◽  
Viral Immunity ◽  
Mait Cells

AbstractCOVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

scholarly journals Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3578
Author(s):  
Emilie Barsac ◽  
Carolina de Amat Herbozo ◽  
Loïc Gonzalez ◽  
Thomas Baranek ◽  
Thierry Mallevaey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Cell Biology ◽  
Therapeutic Potential ◽  
Γδ T Cells ◽  
Feasibility Studies ◽  
T Cell Subsets ◽  
Mait Cells ◽  
Nonpeptide Antigens

The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate–adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.

scholarly journals Identification of leptospiral protein antigens recognized by WC1+ γδ T cell subsets as target for development of recombinant vaccines

2021 ◽  
Author(s):  
Aline Teixeira ◽  
Alexandria Gillespie ◽  
Alehegne Yirsaw ◽  
Emily Britton ◽  
Janice Telfer ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Outer Membrane Proteins ◽  
Γδ T Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Economic Losses ◽  
Γδ T Cell ◽  
Protein Antigens

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+ γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.

scholarly journals A possible role of immunopathogenesis in COVID-19 progression

2020 ◽  
Author(s):  
Moritz Anft ◽  
Krystallenia Paniskaki ◽  
Arturo Blazquez-Navarro ◽  
Adrian Doevelaar ◽  
Felix S. Seibert ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Humoral Immunity ◽  
Viral Infections ◽  
Cell Subset ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Clear Correlation

AbstractBackgroundThe efficacy of the humoral and cellular immunity determines the outcome of viral infections. An appropriate immune response mediates protection, whereas an overwhelming immune response has been associated with immune-mediated pathogenesis in viral infections. The current study explored the general and SARS-CoV-2 specific cellular and humoral immune status in patients with different COVID-19 severities.MethodsIn this prospective study, we included 53 patients with moderate, severe, and critical COVID-19 manifestations comparing their quantitative, phenotypic, and functional characteristics of circulating immune cells, SARS-CoV-2 antigen specific T-cells, and humoral immunity.ResultsSignificantly diminished frequencies of CD8+T-cells, CD4+ and CD8+T-cell subsets with activated differentiated memory/effector phenotype and migratory capacity were found in circulation in patients with severe and/or critical COVID-19 as compared to patients with moderate disease. Importantly, the improvement of the clinical courses from severe to moderate was accompanied by an improvement in the T-cell subset alterations. Furthermore, we surprisingly observed a detectable SARS-CoV-2-reactive T-cell response in all three groups after stimulation with SARS-CoV-2 S-protein overlapping peptide pool already at the first visit. Of note, patients with a critical COVID-19 demonstrated a stronger response of SARS-CoV-2-reactive T-cells producing Th1 associated inflammatory cytokines. Furthermore, clear correlation between antibody titers and SARS-CoV-2-reactive CD4+ frequencies underscore the role of specific immunity in disease progression.ConclusionOur data demonstrate that depletion of activated memory phenotype circulating T-cells and a strong SARS-CoV-2-specific cellular and humoral immunity are associated with COVID-19 disease severity. This counter-intuitive finding may have important implications for diagnostic, therapeutic and prophylactic COVID-19 management.

scholarly journals Recruitment of Neutrophils Mediated by Vγ2 γδ T Cells Deteriorates Liver Fibrosis Induced by Schistosoma japonicum Infection in C57BL/6 Mice

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Li Zheng ◽  
Yuan Hu ◽  
Yanjuan Wang ◽  
Xibao Huang ◽  
Yuxin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Fibrosis ◽  
Schistosoma Japonicum ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Interleukin 17 ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Conventional adaptive T cell responses contribute to the pathogenesis of Schistosoma japonicum infection, leading to liver fibrosis. However, the role of gamma-delta (γδ) T cells in this disease is less clear. γδ T cells are known to secrete interleukin-17 (IL-17) in response to infection, exerting either protective or pathogenic functions. In the present study, mice infected with S. japonicum are used to characterize the role of γδ T cells. Combined with the infection of S. japonicum, an extremely significant increase in the percentage of neutrophils in the CD45+ cells was detected (from approximately 2.45% to 46.10% in blood and from 0.18% to 7.34% in spleen). Further analysis identified two different γδ T cell subsets that have different functions in the formation of granulomas in S. japonicum-infected mice. The Vγ1 T cells secrete gamma interferon (IFN-γ) only, while the Vγ2 T cells secrete both IL-17A and IFN-γ. Both subtypes lose the ability to secrete cytokine during the late stage of infection (12 weeks postinfection). When we depleted the Vγ2 T cells in infected mice, the percentage of neutrophils in blood and spleen decreased significantly, the liver fibrosis in the granulomas was reduced, and the level of IL-17A in the serum decreased (P < 0.05). These results suggest that during S. japonicum infection, Vγ2 T cells can recruit neutrophils and aggravate liver fibrosis by secreting IL-17A. This is the first report that a subset of γδ T cells plays a partial role in the pathological process of schistosome infection.

scholarly journals Antigen-Specific T Cells and Cytokines Detection as Useful Tool for Understanding Immunity against Zoonotic Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Annalisa Agnone ◽  
Alessandra Torina ◽  
Gesualdo Vesco ◽  
Sara Villari ◽  
Fabrizio Vitale ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Crucial Role ◽  
T Cell Subsets ◽  
Host Immune Responses ◽  
Zoonotic Infections ◽  
Immunological Mechanisms

Zoonoses include a broad range of diseases, that are becoming of great interest, due to the climate changing, that cause the adaptation of vectors to new niches and environments. Host immune responses play a crucial role in determining the outcome of infections, as documented by expansion of antigen-specific T cells during several zoonotic infections. Thus, understanding of the contribution of antigen-specific T-cell subsets in the host immune response is a powerful tool to evaluate the different immunological mechanisms involved in zoonotic infections and for the development of effective vaccines. In this paper we discuss the role of T cells in some eukaryotic and prokaryotic infectious models.

scholarly journals CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ahmed Gaballa ◽  
Lucas C. M. Arruda ◽  
Emelie Rådestad ◽  
Michael Uhlin
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Gene Segment ◽  
Adaptive Immune Response ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Adaptive Immune

The role of gamma delta (γδ) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of γδ T cells in response to HCMV, shedding light on the adaptive immune response of γδ T cells. Nevertheless, most efforts have focused on Vδ2negγδ T cell subset while less attention has been given to investigate other less common γδ T cell subsets. In this regard, a distinct subpopulation of γδ T cells that expresses the CD8 coreceptor (CD8+γδ T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR γ-chain (TRG) to analyze in-depth bone marrow (BM) graft γδ T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8+γδ T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8+γδ T cells from CMV+ grafts express Vγ9- and preferentially differentiated from a naive to terminal effector memory phenotype (CD27low/-CD45RO-). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the Vγ9/JP gene segment in a CMV+ graft. Furthermore, CD8+γδ T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8-γδ T cells. We conclude that γδ T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8+γδ T cells in HCMV immune response.

scholarly journals Role of Innate-like Lymphocytes in the Pathogenesis of Community Acquired Pneumonia

2018 ◽  
Author(s):  
RF Hannaway ◽  
X Wang ◽  
M Schneider ◽  
S Slow ◽  
MR Schofield ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bacterial Load ◽  
Γδ T Cells ◽  
Community Acquired Pneumonia ◽  
Cell Abundance ◽  
Mait Cells ◽  
Bacterial Aetiology ◽  
Mait Cell

AbstractBackgroundMucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells are anti-bacterial innate-like lymphocytes (ILLs) that are enriched in blood and mucosa. ILLs have been implicated in control of bacterial infection. However, the role of ILLs in community-acquired pneumonia (CAP) is unknown.MethodsUsing sputum samples from a well-characterised CAP cohort, MAIT cell (Vα7.2-Jα12/20/33) and Vδ2+ T cell (Vδ2-Jδ1/2/3/4) abundance was determined by quantitative PCR. Cytokine and chemokine concentrations in sputum were measured. The capacity of bacteria in sputum to produce activating ligands for MAIT cells and Vδ2+ T cells was inferred by 16S rRNA sequencing.ResultsMAIT cell abundance in sputum was higher in patients with less severe pneumonia; duration of hospital admission was inversely correlated with both MAIT and Vδ2+ T cell abundance. The abundance of both ILLs was higher in patients with a confirmed bacterial aetiology, however there was no correlation with total bacterial load or the predicted capacity of bacteria to produce activating ligands. Sputum MAIT cell abundance was associated with interferon- α, and interferon-γ, and sputum neutrophil abundance, while Vδ2+ T cell abundance was associated with CXCL11 and interferon-γ.ConclusionsPulmonary MAIT and Vδ2+ T cells can be detected in sputum in CAP, where they may contribute to improved clinical outcome.

scholarly journals Revisiting the Role of γδ T Cells in Anti-CMV Immune Response after Transplantation

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1031
Author(s):  
Ahmed Gaballa ◽  
Faisal Alagrafi ◽  
Michael Uhlin ◽  
Arwen Stikvoort
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Post Transplantation ◽  
Tcr Repertoire ◽  
Next Generation Sequencing Ngs

Gamma delta (γδ) T cells form an unconventional subset of T lymphocytes that express a T cell receptor (TCR) consisting of γ and δ chains. Unlike conventional αβ T cells, γδ T cells share the immune signature of both the innate and the adaptive immunity. These features allow γδ T cells to act in front-line defense against infections and tumors, rendering them an attractive target for immunotherapy. The role of γδ T cells in the immune response to cytomegalovirus (CMV) has been the focus of intense research for several years, particularly in the context of transplantation, as CMV reactivation remains a major cause of transplant-related morbidity and mortality. Therefore, a better understanding of the mechanisms that underlie CMV immune responses could enable the design of novel γδ T cell-based therapeutic approaches. In this regard, the advent of next-generation sequencing (NGS) and single-cell TCR sequencing have allowed in-depth characterization of CMV-induced TCR repertoire changes. In this review, we try to shed light on recent findings addressing the adaptive role of γδ T cells in CMV immunosurveillance and revisit CMV-induced TCR reshaping in the era of NGS. Finally, we will demonstrate the favorable and unfavorable effects of CMV reactive γδ T cells post-transplantation.

scholarly journals Cryopreservation of Whole Tumor Biopsies from Rectal Cancer Patients Enable Phenotypic and In Vitro Functional Evaluation of Tumor-Infiltrating T Cells

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2428
Author(s):  
Frank Liang ◽  
Azar Rezapour ◽  
Peter Falk ◽  
Eva Angenete ◽  
Ulf Yrlid
Keyword(s):  
Rectal Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Functional Evaluation ◽  
Mait Cells ◽  
Ifn Γ ◽  
Tumor Biopsies

TILs comprise functionally distinct conventional and unconventional T cell subsets and their role in responses to CRC treatments is poorly understood. We explored recovery of viable TILs from cryopreserved tumor biopsies of (chemo)-radiated patients with rectal cancer to establish a platform for retrospective TIL analyses of frozen tumors from pre-selected study cohorts. Frequencies of TIL subsets and their capacity to mount IFN-γ responses in cell suspensions of fresh vs. cryopreserved portions of the same tumor biopsies were determined for platform validation. The percentages and proportions of CD4+ TILs and CD8+ cytotoxic T lymphocytes (CTLs) among total TILs were not affected by cryopreservation. While recovery of unconventional γδ T cells and mucosal-associated invariant T cells (MAIT cells) was stable after cryopreservation, the regulatory T cells (Tregs) were reduced, but in sufficient yields for quantification. IFN-γ production by in vitro-stimulated CD4+ TILs, CTLs, γδ T cells, and MAIT cells were proportionally similar in fresh and cryopreserved tumor portions, albeit the latter displayed lower levels. Thus, the proposed platform intended for TIL analyses on cryopreserved tumor biobank biopsies holds promises for studies linking the quantity and quality of TIL subsets with specific clinical outcome after CRC treatment.

scholarly journals CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

2021 ◽  
Vol 9 (4) ◽  
pp. e002051
Author(s):  
Ryan Michael Reyes ◽  
Yilun Deng ◽  
Deyi Zhang ◽  
Niannian Ji ◽  
Neelam Mukherjee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Combination Treatment ◽  
Treatment Efficacy ◽  
Interleukin 2 ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell

BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

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