Lymphopenia in COVID-19: γδ T Cells-Based Therapeutic Opportunities

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dysregulates the immune system by lymphopenia of B cells, monocytes, eosinophils, basophils, and cytotoxic cells such as CD8, γδ T cells, and natural killer (NK) cells. Despite many studies being conducted to better understand the effects of SARS-CoV-2 on the immune system, many mechanisms still remain unclear, hindering the development of novel therapeutic approaches and strategies to improve the host’s immune defense. This mini-review summarizes the findings on the role of γδ T cells in coronavirus disease 2019 (COVID-19), providing an overview of the excellent anti-viral therapeutic potential of γδ T cells, that had not yet been exploited in depth.

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The Role of Progesterone in Feto-Maternal Immunological Cross Talk

Medical Principles and Practice ◽

10.1159/000491576 ◽

2018 ◽

Vol 27 (4) ◽

pp. 301-307 ◽

Cited By ~ 21

Author(s):

Julia Szekeres-Bartho

Keyword(s):

T Cells ◽

Immune System ◽

Nk Cells ◽

Hla Antigens ◽

Γδ T Cells ◽

Normal Pregnancy ◽

Maternal Immune System ◽

Immunological Recognition ◽

Immunological Relationship

This review aims to provide a brief historical overview of the feto-maternal immunological relationship, which profoundly influences the outcome of pregnancy. The initial question posed in the 1950s by Medawar [Symp Soc Exp Biol. 1953; 7: 320–338] was based on the assumption that the maternal immune system recognizes the fetus as an allograft. Indeed, based on the association between HLA-matching and spontaneous miscarriage, it became obvious that immunological recognition of pregnancy is required for a successful gestation. The restricted expression of polymorphic HLA antigens on the trophoblast, together with the presence of nonpolymorphic MHC products, excludes recognition by both T and NK cells of trophoblast-presented antigens; however, γδ T cells, which constitute the majority of decidual T cells, are likely candidates. Indeed, a high number of activated, progesterone receptor-expressing γδ T cells are present in the peripheral blood of healthy pregnant women and, in the presence of progesterone, these cells secrete an immunomodulatory protein called progesterone-induced blocking factor (PIBF). As early as in the peri-implantation period, the embryo communicates with the maternal immune system via PIBF containing extracellular vesicles. PIBF contributes to the dominance of Th2-type reactivity which characterizes normal pregnancy by inducing increased production of Th2 cytokines. The high expression of this molecule in the decidua might be one of the reasons for the low cytotoxic activity of decidual NK cells.

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The role of antigen recognition in the γδ T cell response at the controlled stage of M. tuberculosis infection.

10.1101/2021.09.14.460324 ◽

2021 ◽

Author(s):

Roshni Roy Chowdhury ◽

John R Valainis ◽

Oliver Kask ◽

Mane Ohanyan ◽

Meng Sun ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Specific Antigen ◽

Γδ T Cells ◽

T Cell Response ◽

Immune Defense ◽

Γδ T Cell ◽

Antigenic Exposure

γδ T cells contribute to host immune defense uniquely; but how they function in different stages (e.g., acute versus chronic) of a specific infection remains unclear. As the role of γδ T cells in early, active Mycobacterium tuberculosis (Mtb) infection is well documented, we focused on elucidating the γδ T cell response in persistent or controlled Mtb infection. Systems analysis of circulating gd T cells from a South African adolescent cohort identified a distinct population of CD8+ γδ T cells that expanded in this state. These cells had features indicative of persistent antigenic exposure but were robust cytolytic effectors and cytokine/chemokine producers. While these γδ T cells displayed an attenuated response to TCR-mediated stimulation, they expressed Natural Killer (NK) cell receptors and had robust CD16 (FcgRIIIA)-mediated cytotoxic response, suggesting alternative ways for gd T cells to control this stage of the infection. Despite this NK-like functionality, the CD8+ γδ T cells consisted of highly expanded clones, which utilized TCRs with different Vg/d pairs. Theses TCRs could respond to an Mtb-lysate, but not to phosphoantigens, which are components of Mtb-lysate that activate gd T cells in acute Mtb infection, indicating that the CD8+ γδ T cells were induced in a stage-specific, antigen-driven manner. Indeed, trajectory analysis showed that these γδ T cells arose from naive cells that had traversed distinct differentiation paths in this infection stage. Importantly, increased levels of CD8+ γδ T cells were also found in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may lead to similar γδ T cell responses.

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Neoantigens in cancer immunotherapy

Science ◽

10.1126/science.aaa4971 ◽

2015 ◽

Vol 348 (6230) ◽

pp. 69-74 ◽

Cited By ~ 2046

Author(s):

Ton N. Schumacher ◽

Robert D. Schreiber

Keyword(s):

Immune Response ◽

T Cells ◽

Immune System ◽

Cancer Immunotherapy ◽

Patient Specific ◽

Technological Innovations ◽

Therapeutic Approaches ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Novel Therapeutic

The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens.

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Targeting FOXOs to slow aging

Molecular inhibitors in targeted therapy ◽

10.1515/motth-2015-0003 ◽

2015 ◽

Vol 1 (1) ◽

Author(s):

Rute Martins ◽

Kathleen J. Dumas ◽

Gordon J. Lithgow

Keyword(s):

Immune System ◽

Aging Process ◽

Therapeutic Approaches ◽

Health Span ◽

Immune System Dysfunction ◽

Foxo Transcription Factors ◽

Near Future ◽

Fertile Area ◽

Novel Therapeutic

Abstract:The key importance of FOXO transcription factors and related pathways in the process of aging renders them compelling targets in the quest for compounds that could slow down the aging process. In this review, we give a brief overview of what we know about the role of FOXO proteins in aging and longevity and describe how this knowledge might be of value in developing future therapies aimed at extending lifespan and health span in people. Given the potential of FOXO proteins to impact on a variety of disorders such as cancer, diabetes, neurodegeneration or immune system dysfunction, novel therapeutic approaches based FOXO-targeting strategies are expected to be a fertile area of research in the near future.

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Faculty Opinions recommendation of γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736003602.793573522 ◽

2020 ◽

Author(s):

David Wiest ◽

Alejandra Contreras

Keyword(s):

T Cells ◽

Therapeutic Potential ◽

Γδ T Cells

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Thromboses and Hemostasis Disorders Associated with Coronavirus Disease 2019: The Possible Causal Role of Cross-Reactivity and Immunological Imprinting

Global Medical Genetics ◽

10.1055/s-0041-1731068 ◽

2021 ◽

Author(s):

Darja Kanduc

Keyword(s):

Immune System ◽

Severe Acute Respiratory Syndrome ◽

Natural Infection ◽

Vascular Diseases ◽

Cross Reactivity ◽

Active Immunization ◽

Thromboembolic Complications ◽

Human Proteins ◽

Almost All

AbstractBy examining the issue of the thromboses and hemostasis disorders associated with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) through the lens of cross-reactivity, it was found that 60 pentapeptides are shared by SARS-CoV-2 spike glycoprotein (gp) and human proteins that— when altered, mutated, deficient or, however, improperly functioning— cause vascular diseases, thromboembolic complications, venous thrombosis, thrombocytopenia, coagulopathies, and bleeding, inter alia. The peptide commonality has a relevant immunological potential as almost all of the shared sequences are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes, thus supporting the possibility of cross-reactions between the viral gp and the thromboses-related human proteins. Moreover, many of the shared peptide sequences are also present in pathogens to which individuals have previously been exposed following natural infection or vaccinal routes, and of which the immune system has stored imprint. Such an immunological memory might rapidly trigger anamnestic secondary cross-reactive responses of extreme affinity and avidity, in this way explaining the thromboembolic adverse events that can associate with SARS-CoV-2 infection or active immunization.

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The role of unconventional T cells in COVID-19

Irish Journal of Medical Science (1971 -) ◽

10.1007/s11845-021-02653-9 ◽

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.

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Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

Cancers ◽

10.3390/cancers13143578 ◽

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.

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