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 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 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 Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Sergej Tomić ◽  
Jelena Đokić ◽  
Dejan Stevanović ◽  
Nataša Ilić ◽  
Alisa Gruden-Movsesijan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Response ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Myeloid Derived Suppressor Cells ◽  
Immunological Mechanisms

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.

CD4+CD25+ Regulatory T Cells Control Induction of Autoimmune Hemolytic Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 579-579
Author(s):  
Karina Yazdanbakhsh ◽  
Amina Mqadmi ◽  
Xiaoying Zheng
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Repeated Injection ◽  
Autoantibody Production

Abstract Autoimmune Hemolytic anemia (AIHA) is the result of increased destruction of red blood cells (RBCs) due to the production of antibodies against self antigens. Anemia can be severe and life-threatening. The underlying mechanism of autoimmunity is the result of breakdown of immune tolerance, but the molecular and cellular basis for the induction of AIHA remains to be fully defined. To further our understanding of mechanisms that trigger AIHA, we used the Marshall-Clarke and Playfair model of murine AIHA. Anemia is induced by repeated injection of rat RBCs resulting in development of erythrocyte autoantibodies as well as rat-specific immunoglobulins. The severity of the autoimmune disease is strain dependent. We found that in about 20–30% of C57/Bl6 mice repeatedly immunized with washed rat RBCs, there is breakdown of tolerance and development of pathogenic autoantibodies resulting in decreased hematocrit, reticulocytosis and increased destruction of transfused syngeneic mouse RBCs. To identify the immunological factors contributing to the incidence of AIHA, we analyzed the role of specific T regulatory subsets in controlling AIHA in C57/Bl6 mice. Previous studies documented that depletion of selected regulatory CD4+ T cell subsets (CD25+, CD62L+ and CD45RBlow) can induce different degrees of autoimmune disorders. However, the nature of the regulatory T cell subset in the induction of AIHA has not yet been studied. To test the role of CD25+ T regulatory cells in the induction of AIHA, 10 week old C57/Bl6 mice (n=10) were treated with 500 μg of anti-CD25 antibody six hours prior to immunization with rat RBCs on a weekly basis for four weeks. Following this repeated challenge the incidence of AIHA increased from 20 to 90%. Treatment with isotype control antibody prior to weekly injections of rat RBCs for four weeks resulted in the expected 20% incidence of AIHA. Furthermore, weekly treatment with anti-CD25 alone for four weeks did not result in development of AIHA, indicating that the depletion of CD25 cells in combination with rat RBC stimulus was important for the development AIHA. To test whether anti-CD25 treatment also increased the levels of autoantibodies directed against other non-erythroid antigens, we measured the levels of antibodies to double stranded DNA (anti-ds DNA) characteristic of systemic autoimmune disease and found significantly elevated levels in anti-CD25/rat RBC immunized mice, as compared to control mice treated with rat RBCs alone. Interestingly, treatment with anti-CD25 alone did not result in increased levels of anti-ds DNA, indicating that selective depletion of CD25+ does not result in the development of autoimmunity and that an additional signal is required to activate autoreactivity. In addition, the levels of alloantibodies against rat RBCs in anti-CD25/rat RBC immunized mice were elevated as compared to mice treated with rat RBCs alone, consistent with a heightened immune hypersensitive state. Importantly, adoptive transfer of purified splenic population of CD4+CD25+ from mice that had undergone weekly injections of rat erythrocytes for 12 weeks into naïve C57/Bl6 mice (n=5) prevented the induction of autoantibody production whereas transfer of CD4+CD25-T cells into naïve mice (n=6) significantly elevated the autoantibody levels following weekly immunization with rat RBCs. These findings emphasize an important suppressive role for CD4+CD25+ in prevention of AIHA. Altogether, our data provide new insight regarding the mechanism for breakdown of tolerance in antibody-mediated autoimmunes disease which may help to establish therapeutic strategies for treatment of AIHA.

scholarly journals Age related human T cell subset evolution and senescence

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Mingde Li ◽  
Danlin Yao ◽  
Xiangbo Zeng ◽  
Dimitri Kasakovski ◽  
Yikai Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Cell Subset ◽  
Absolute Number ◽  
T Cell Subsets ◽  
And Gender

Abstract T cells are fundamental effector cells against viruses and cancers that can be divided into different subsets based on their long-term immune protection and immediate immune response effects. The percentage and absolute number of these subsets change with ageing, which leads to a reduced immune response in older individuals. Stem cell memory T cells (TSCM) represent a small population of memory T cells with enhanced proliferation and differentiation properties that are endowed with high potential for maintaining T cell homeostasis. However, whether these cells change with ageing and gender remains unknown. Here, we assayed the distribution of TSCM and other T cell subsets in peripheral blood from 92 healthy subjects (44 females and 48 males) ranging from 3 to 88 years old by flow cytometry. We found that CD4+ and CD8+ TSCM in the circulation have relatively stable frequencies, and the absolute number of CD8+ TSCM decreased with age; however, the ratio of TSCM to the CD4+ or CD8+ naïve population increased with age. Unlike the obvious changes in other T cell subsets with age and gender, the stable level of TSCM in peripheral blood may support their capacity for sustaining long-term immunological memory, while their importance may increase together with ageing.

scholarly journals CD8lowCD100−T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

2015 ◽  
Vol 89 (23) ◽  
pp. 11834-11844 ◽  
Author(s):  
Bei Liu ◽  
Ying Ma ◽  
Yusi Zhang ◽  
Chunmei Zhang ◽  
Jing Yi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Early Phase ◽  
Late Phase ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Hantaan Virus ◽  
Viral Control

ABSTRACTHantaan virus (HTNV) infection can cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. CD8+T cells play a critical role in combating HTNV infections. However, the contributions of different CD8+T cell subsets to the immune response against viral infection are poorly understood. Here, we identified a novel subset of CD8+T cells characterized by the CD8lowCD100−phenotype in HFRS patients. The CD8lowCD100−subset accounted for a median of 14.3% of the total CD8+T cells in early phase of HFRS, and this percentage subsequently declined in the late phase of infection, whereas this subset was absent in healthy controls. Furthermore, the CD8lowCD100−cells were associated with high activation and expressed high levels of cytolytic effector molecules and exhibited a distinct expression profile of effector CD8+T cells (CCR7+/−CD45RA−CD127highCD27intCD28lowCD62L−). When stimulated with specific HTNV nucleocapsid protein-derived peptide pools, most responding CD8+cells (gamma interferon [IFN-γ] positive and/or tumor necrosis factor alpha [TNF-α] positive) were CD8lowCD100−cells. The frequency of CD8lowCD100−cells among HTNV-specific CD8+T cells was higher in milder cases than in more severe cases. Importantly, the proportion of the CD8lowCD100−subset among CD8+T cells in early phase of HFRS was negatively correlated with the HTNV viral load, suggesting that CD8lowCD100−cells may be associated with viral clearance. The contraction of the CD8lowCD100−subset in late phase of infection may be related to the consistently high expression levels of PD-1. These results may provide new insights into our understanding of CD8+T cell-mediated protective immunity as well as immune homeostasis after HTNV infection in humans.IMPORTANCECD8+T cells play important roles in the antiviral immune response. We found that the proportion of CD8lowCD100−cells among CD8+T cells from HFRS patients was negatively correlated with the HTNV viral load, and the frequency of CD8lowCD100−cells among virus-specific CD8+T cells was higher in milder HFRS cases than in more severe cases. These results imply a beneficial role for the CD8lowCD100−cell subset in viral control during human HTNV infection.

scholarly journals Regulation of T Cells in Cancer by Nitric Oxide

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2655
Author(s):  
Inesa Navasardyan ◽  
Benjamin Bonavida
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Functions

The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.

scholarly journals Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhilin Peng ◽  
Yiwen Zhang ◽  
Xiancai Ma ◽  
Mo Zhou ◽  
Shiyu Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Type I ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Antigen Stimulation

CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.

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.

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