Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Anna von Rossum ◽  
Winnie Enns ◽  
Yu P Shi ◽  
Jonathan C Choy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Intimal Thickening ◽  
Cell Responses ◽  
Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

scholarly journals A262 DIFFERENTIAL PHENOTYPES AND LOCALIZATION OF CD8+ T CELL RESPONSES TO ACUTE AND CHRONIC ENTERIC VIRAL INFECTION

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 139-140
Author(s):  
B K Hardman ◽  
L C Osborne
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Post Infection ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses

Abstract Background Human Norovirus infection is the most common viral cause of gastroenteritis globally and the second most reported viral infection in Canada after the common cold. Most infections are acute, symptomatic, and rapidly cleared but some cases persist asymptomatically or induce post-infectious irritable bowel syndrome. Despite the global burden of these infections, no vaccine to prevent disease exists nor is the mechanism for persistence understood. MNV-CW3 and MNV-CR6 are murine noroviruses which demonstrate distinct biological behaviors that correlate with differential quantity and quality of antiviral CD8+ T cell responses. MNV-CW3 causes acute systemic infections initiated in the small intestine and cleared by day 8 due to a robust antiviral CD8+ T cell response. In contrast, MNV-CR6 causes chronic infections localized to the colonic intestinal epithelium and induces fewer antiviral CD8+ T cells with reduced effector molecule expression. Aims This research interrogates the mechanisms underlying strain-specific differential antiviral CD8+ T cell responses. Methods At days 3, 4, 5 and 8 post-infection, the phenotype and quantity of adoptively transferred MNV specific CD8+ T cells in the spleen, mesenteric lymph node (MLN), and the small and large intestine are analyzed by flow cytometry. Concurrently, immunofluorescent microscopy is used to determine whether CD8+ T cells are broadly disseminated throughout the intestines or localize in acute clusters of antiviral response. Combining these complementary techniques provides novel insight into mechanisms governing intestinal antiviral T cell responses. Results Activated MNV-specific CD8 T cells first accumulate in the MLN following oral infection with both MNV-CW3 and CR6, suggesting this is the site of immune activation. Supporting this hypothesis, preliminary data indicates that preventing T cell egress from activation sites by treatment with the S1PR1 agonist FTY720 leads to an enrichment of activated CD8+ T cells in the MLN following CW3 infection. Notably, the earliest stages of CD8+ T cell activation to CR6 infection is delayed compared to that elicited by CW3. Furthermore, at the peak of CD8+ T cell expansion (day 8 post-infection), CR6-elicited CD8+ T cells preferentially develop into short-lived effector populations rather than memory precursor populations. Conclusions These data reveal previously unknown differences in early events in CD8+ T cell activation following infection with two highly related viral strains that correlate with long-lasting effects on T cell differentiation and function. We are currently investigating the hypothesis that MNV-CW3 and CR6 may induce activation of distinct populations of, or pathways in, APC populations that would drive these differences. These results may have broad impacts on our understanding of how non-latent, chronic viral infections persist within a host. Funding Agencies CIHR

scholarly journals Role of Lymphotoxin α in T-Cell Responses during an Acute Viral Infection

2002 ◽  
Vol 76 (8) ◽  
pp. 3943-3951 ◽  
Author(s):  
M. Suresh ◽  
Gibson Lanier ◽  
Mary Katherine Large ◽  
Jason K. Whitmire ◽  
John D. Altman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Lymphotoxin Α

ABSTRACT The importance of lymphotoxin α (LTα) in lymphoid organogenesis is well established. Although LTα has been implicated in the pathogenesis of T-cell-mediated immunopathologies, the requirement for LTα in T-cell activation and effector function in vivo is not well understood. To determine the role of LTα in T-cell activation in vivo, we compared the generation of antigen-specific T-cell responses between wild type (+/+) and LTα-deficient (LTα−/−) mice during an acute infection with lymphocytic choriomeningitis virus (LCMV). Our studies showed that LCMV-infected LTα−/− mice had a profound impairment in the activation and expansion of virus-specific CD8 T cells in the spleen, as determined by cytotoxicity assays, intracellular staining for gamma interferon, and staining with major histocompatibility complex class I tetramers. Further, the nonlymphoid organs of LTα−/− mice also contained substantially lower number of LCMV-specific CD8 T cells than those of +/+ mice. Greatly reduced virus-specific CD8 T-cell responses in LTα−/− mice led to a defect in LCMV clearance from the tissues. In comparison to that in +/+ mice, the activation of LCMV-specific CD4 T cells was also significantly attenuated in LTα−/− mice. Adoptive transfer experiments were conducted to determine if abnormal lymphoid architecture in LTα−/− mice caused the impairment in the activation of LCMV-specific T-cell responses. Upon adoptive transfer into +/+ mice, the activation and expansion of LCMV-specific LTα−/− T cells were restored to levels comparable to those of +/+ T cells. In a reciprocal cell transfer experiment, activation of +/+ T cells was significantly reduced upon transfer into LTα−/− mice. These results showed that impairment in the activation of LCMV-specific T cells in LTα−/− mice may be due to abnormal lymphoid architecture and not to an intrinsic defect in LTα−/− T cells.

scholarly journals 2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses

2014 ◽  
Vol 211 (2) ◽  
pp. 297-311 ◽  
Author(s):  
Danya Liu ◽  
Scott M. Krummey ◽  
I. Raul Badell ◽  
Maylene Wagener ◽  
Lumelle A. Schneeweis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Modulation ◽  
Cell Activation ◽  
Critical Role ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses

Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8+ T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8+ T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti–CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8+ T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8+ T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8+ effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8+ T cell responses.

scholarly journals High Frequencies of Functional Virus-Specific CD4+ T Cells in SARS-CoV-2 Subjects With Olfactory and Taste Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Dalila Mele ◽  
Anna Calastri ◽  
Eugenia Maiorano ◽  
Antonella Cerino ◽  
Michele Sachs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Control Group ◽  
Presenting Symptoms ◽  
Cell Responses ◽  
Taste Disorders ◽  
Specific Igg

Olfactory and taste disorders (OTD) are commonly found as presenting symptoms of SARS-CoV-2 infection in patients with clinically mild COVID-19. Virus-specific T cells are thought to play an important role in the clearance of SARS-CoV-2; therefore the study of T cell specific immune responses in patients with mild symptoms may help to understand their possible role in protection from severe disease. We evaluated SARS-CoV-2-specific T cell responses to four different peptide megapools covering all SARS-CoV-2 proteins during the acute phase of the disease in 33 individuals with mild or no other symptom beside OTD and in 22 age-matched patients with severe infection. A control group of 15 outpatients with OTD and consistently negative nasopharyngeal SARS-CoV-2 RNA swabs and virus-specific IgG serology was included in the study. Increased frequencies of virus-specific CD4+ and CD8+ T cells were found in SARS-CoV-2 positive patients with OTD compared with those with severe COVID-19 and with SARS-CoV-2 negative OTD individuals. Moreover, enhanced CD4+ and CD8+ T-cell activation induced by SARS-CoV-2 peptides was associated with higher interferon (IFN)γ production. Increased frequencies of Spike (S1/S2)-specific CD4+ T cells showing enhanced IFNγ secretion and granzyme B content were associated with serum spike-specific IgG in the OTD group. In conclusion, patients with SARS-CoV-2 induced OTD develop highly functional virus-specific CD4+ and CD8+ T cells during the symptomatic phase of the disease, suggesting that robust and coordinated T-cell responses provide protection against extension of COVID-19 to the lower respiratory tract.

scholarly journals Vector Order Determines Protection against Pathogenic Simian Immunodeficiency Virus Infection in a Triple-Component Vaccine by Balancing CD4+ and CD8+ T-Cell Responses

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Ulrike Sauermann ◽  
Antonia Radaelli ◽  
Nicole Stolte-Leeb ◽  
Katharina Raue ◽  
Massimiliano Bissa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Target Cells ◽  
Aids Vaccine ◽  
Cell Responses ◽  
Antibody Titers

ABSTRACT An effective AIDS vaccine should elicit strong humoral and cellular immune responses while maintaining low levels of CD4+ T-cell activation to avoid the generation of target cells for viral infection. The present study investigated two prime-boost regimens, both starting vaccination with single-cycle immunodeficiency virus, followed by two mucosal boosts with either recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 gag/pol and env genes, respectively. Finally, vectors were switched and systemically administered to the reciprocal group of animals. Only mucosal rFWPV immunizations followed by systemic rAd boost significantly protected animals against a repeated low-dose intrarectal challenge with pathogenic SIVmac251, resulting in a vaccine efficacy (i.e., risk reduction per exposure) of 68%. Delayed viral acquisition was associated with higher levels of activated CD8+ T cells and Gag-specific gamma interferon (IFN-γ)-secreting CD8+ cells, low virus-specific CD4+ T-cell responses, and low Env antibody titers. In contrast, the systemic rFWPV boost induced strong virus-specific CD4+ T-cell activity. rAd and rFWPV also induced differential patterns of the innate immune responses, thereby possibly shaping the specific immunity. Plasma CXCL10 levels after final immunization correlated directly with virus-specific CD4+ T-cell responses and inversely with the number of exposures to infection. Also, the percentage of activated CD69+ CD8+ T cells correlated with the number of exposures to infection. Differential stimulation of the immune response likely provided the basis for the diverging levels of protection afforded by the vaccine regimen. IMPORTANCE A failed phase II AIDS vaccine trial led to the hypothesis that CD4+ T-cell activation can abrogate any potentially protective effects delivered by vaccination or promote acquisition of the virus because CD4+ T helper cells, required for an effective immune response, also represent the target cells for viral infection. We compared two vaccination protocols that elicited similar levels of Gag-specific immune responses in rhesus macaques. Only the animal group that had a low level of virus-specific CD4+ T cells in combination with high levels of activated CD8+ T cells was significantly protected from infection. Notably, protection was achieved despite the lack of appreciable Env antibody titers. Moreover, we show that both the vector and the route of immunization affected the level of CD4+ T-cell responses. Thus, mucosal immunization with FWPV-based vaccines should be considered a potent prime in prime-boost vaccination protocols.

scholarly journals Visualising the interaction of CD4 T cells and DCs in the evolution of inflammatory arthritis

2018 ◽  
Vol 77 (4) ◽  
pp. 579-588 ◽  
Author(s):  
Catriona T Prendergast ◽  
Agapitos Patakas ◽  
Shaima Al-Khabouri ◽  
Claire L McIntyre ◽  
Iain B McInnes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Receptor Expression ◽  
Phenotypic Analysis ◽  
Necrosis Factor Alpha ◽  
Cell Responses

ObjectivesSuccessful early intervention in rheumatoid arthritis (RA) with the aim of resetting immunological tolerance requires a clearer understanding of how specificity, cellular kinetics and spatial behaviour shape the evolution of articular T cell responses. We aimed to define initial seeding of articular CD4+ T cell responses in early experimental arthritis, evaluating their dynamic behaviour and interactions with dendritic cells (DCs) in the inflamed articular environment.MethodsAntigen-induced arthritis was used to model articular inflammation. Flow cytometry and PCR of T cell receptor (TCR) diversity genes allowed phenotypic analysis of infiltrating T cells. The dynamic interactions of T cells with joint residing DCs were visualised using intravital multiphoton microscopy.ResultsInitial recruitment of antigen-specific T cells into the joint was paralleled by accumulation of CD4+ T cells with diverse antigen-receptor expression and ability to produce tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) on mitogenic restimulation. A proportion of this infiltrate demonstrated slower motility speeds and engaged for longer periods with articular DCs in vivo. Abatacept treatment did not disrupt these interactions but did reduce T cell expression of inducible costimulatory (ICOS) molecule. We also demonstrated that non-specific CD4+ T cells could be recruited during these early articular events.ConclusionsWe demonstrate that CD4+ T cells engage with articular DCs supporting antigen specific T cell reactivation. This cellular dialogue can be targeted therapeutically to reduce local T cell activation.

Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 606-615 ◽  
Author(s):  
Cristina Cerboni ◽  
Alessandra Zingoni ◽  
Marco Cippitelli ◽  
Mario Piccoli ◽  
Luigi Frati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Protein A ◽  
T Cell Responses ◽  
Activated T Cells ◽  
Cell Responses

AbstractRecent evidence indicates that natural killer (NK) cells can negatively regulate T-cell responses, but the mechanisms behind this phenomenon as a consequence of NK–T-cell interactions are poorly understood. We studied the interaction between the NKG2D receptor and its ligands (NKG2DLs), and asked whether T cells expressed NKG2DLs in response to superantigen, alloantigen, or a specific antigenic peptide, and if this rendered them susceptible to NK lysis. As evaluated by FACS, the major histocompatibility complex (MHC) class I chain-related protein A (MICA) was the ligand expressed earlier on both CD4+ and CD8+ T cells in 90% of the donors tested, while UL16-binding protein-1 (ULBP)1, ULBP2, and ULBP3 were induced at later times in 55%–75% of the donors. By carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, we observed that NKG2DLs were expressed mainly on T cells that had gone through at least one division. Real-time reverse-transcription polymerase chain reaction confirmed the expression of all NKG2DLs, except ULBP4. In addition, T-cell activation stimulated phosphorylation of ataxia-telangiectasia mutated (ATM), a kinase required for NKG2DLs expression after DNA damage, and ATM/Rad3-related kinase (ATR) inhibitors blocked MICA induction on T cells with a mechanism involving NF-κB. Finally, we demonstrated that activated T cells became susceptible to autologous NK lysis via NKG2D/NKG2DLs interaction and granule exocytosis, suggesting that NK lysis of T lymphocytes via NKG2D may be an additional mechanism to limit T-cell responses.

scholarly journals Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression

2007 ◽  
Vol 204 (11) ◽  
pp. 2679-2692 ◽  
Author(s):  
Dennis J. Hartigan-O'Connor ◽  
Kristina Abel ◽  
Joseph M. McCune
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Compartment ◽  
Rapid Disease Progression ◽  
Cell Responses

The impact of regulatory T cells (T reg cells) on the course of HIV and SIV disease is unknown. T reg cells could suppress protective antiviral responses and accelerate disease progression. Alternatively, these cells might block T cell activation and thereby limit viral replication as well as activation-associated immunopathology. Given the higher frequency of T reg cells known to be present during human fetal ontogeny, such influences may be most important in the context of perinatal infection. We found that infant macaques had higher fractions of CD4+CD25+CD127lowFoxP3+ T reg cells in the peripheral blood and in lymphoid tissues, and that these T reg cells showed greater in vitro suppressive activity on a per cell basis. Infant and adult macaques were infected with SIVmac251 to test the influence of the T reg cell compartment on SIV-specific immune responses. After infection with SIV, most (three out of four) infant macaques had persistently high viral loads, weak and transient SIV-specific CD4+ and CD8+ T cell responses, and rapid disease progression. T reg cells in the infant but not in the adult directly suppressed SIV-specific CD4+ T cell responses, which were detectable only after depletion of T reg cells. In the case of both the infant and the adult macaque, T reg cells were not able to directly suppress SIV-specific CD8+ T cell responses and had no apparent effect on T cell activation. In aggregate, these observations suggest that the T reg cell compartment of the infant macaque facilitates rapid disease progression, at least in part by incapacitating SIV-specific CD4+ T cell responses.

scholarly journals CD6 as a potential target for treating multiple sclerosis

2017 ◽  
Vol 114 (10) ◽  
pp. 2687-2692 ◽  
Author(s):  
Yan Li ◽  
Nora G. Singer ◽  
Joy Whitbred ◽  
Michael A. Bowen ◽  
David A. Fox ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Microvascular Endothelial Cell ◽  
Cell Responses ◽  
T Cell Survival

CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell–driven autoimmune conditions.

scholarly journals Yap suppresses T cell function and infiltration in the tumor microenvironment

2019 ◽  
Author(s):  
Eleni Stampouloglou ◽  
Anthony Federico ◽  
Emily Slaby ◽  
Stefano Monti ◽  
Gregory L. Szeto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cell Responses

ABSTRACTA major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+ and CD8+ T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

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