scholarly journals CTLA-4–B7 Interaction Is Sufficient to Costimulate T Cell Clonal Expansion

1997 ◽  
Vol 185 (7) ◽  
pp. 1327-1336 ◽  
Author(s):  
Yan Wu ◽  
Yong Guo ◽  
Andy Huang ◽  
Pan Zheng ◽  
Yang Liu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Critical Role ◽  
Clonal Expansion ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
Cell Clonal Expansion

T cell costimulation, particularly by the B7 family members B7-1 and B7-2, plays a critical role in regulating T cell–mediated immunity. Two molecules on T cells, CD28 and CTLA-4, are known to bind to B7. It has been suggested that CD28–B7 interaction promotes T cell response, whereas B7–CTLA-4 interaction downregulates T cell clonal expansion. However, the proposed responses of individual receptors to B7 have not been verified directly. Here, we report that B7-1 promotes clonal expansion of CD28-deficient T cells, and that the CD28-independent costimulatory activity is mediated by CTLA-4, as it is completely blocked by intact and Fab of anti–CTLA-4 mAb. In addition, a mutant B7-1 molecule, B7W88 >A, which has lost binding to CD28 but retained significant CTLA-4 binding activity, promotes T cell clonal expansion. Furthermore, while presence of CD28 enhances T cell response to B7-1, such response is also completely blocked by anti–CTLA-4 mAb. Taken together, our results demonstrate that B7–CTLA-4 interaction promotes T cell clonal expansion, and that optimal T cell response to B7 is achieved when both CD28 and CTLA-4 interact with B7. These results establish an important function of CTLA-4 in promoting T cell activation, and suggest an alternative interpretation of the function of CTLA-4 in T cell activation.

scholarly journals Gammadelta T Cells Are Required for CD8+ T Cell Response to Vaccinia Viral Infection

2021 ◽  
Author(s):  
Rui Dai ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cell Response ◽  
Critical Role ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Gammadelta T Cells

Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+ T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+ T cell response to VV infection. In this study, we showed that gammadelta T cells play an important role in promoting CD8+ T cell response to VV infection. We found that gammadelta T cells can directly present viral antigens in the context MHC-I for CD8+ T cell activation to VV in vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in gammadelta T cells is required for activation of gammadelta T cells and CD8+ T cells. These results illustrate a critical role for gammadelta T cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of gammadelta T cells.

scholarly journals A gammaherpesvirus-secreted activator of Vβ4+ CD8+ T cells regulates chronic infection and immunopathology

2008 ◽  
Vol 205 (3) ◽  
pp. 669-684 ◽  
Author(s):  
Andrew G. Evans ◽  
Janice M. Moser ◽  
Laurie T. Krug ◽  
Veranika Pozharskaya ◽  
Ana L. Mora ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Murine Gammaherpesvirus

Little is known about herpesvirus modulation of T cell activation in latently infected individuals or the implications of such for chronic immune disorders. Murine gammaherpesvirus 68 (MHV68) elicits persistent activation of CD8+ T cells bearing a Vβ4+ T cell receptor (TCR) by a completely unknown mechanism. We show that a novel MHV68 protein encoded by the M1 gene is responsible for Vβ4+ CD8+ T cell stimulation in a manner reminiscent of a viral superantigen. During infection, M1 expression induces a Vβ4+ effector T cell response that resists functional exhaustion and appears to suppress virus reactivation from peritoneal cells by means of long-term interferon-γ (IFNγ) production. Mice lacking an IFNγ receptor (IFNγR−/−) fail to control MHV68 replication, and Vβ4+ and CD8+ T cell activation by M1 instead contributes to severe inflammation and multiorgan fibrotic disease. Thus, M1 manipulates the host CD8+ T cell response in a manner that facilitates latent infection in an immunocompetent setting, but promotes disease during a dysregulated immune response. Identification of a viral pathogenecity determinant with superantigen-like activity for CD8+ T cells broadens the known repertoire of viral immunomodulatory molecules, and its function illustrates the delicate balance achieved between persistent viruses and the host immune response.

Transient but Reversible Activation Defect of T-Cell Responses Against Cytomegalovirus and Adenovirus through Immunosuppresion with Calcineurin Inhibitors.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4542-4542
Author(s):  
Cornelia Neinhaus ◽  
Kathrin Opherk ◽  
Simone Kayser ◽  
Joseph Leibold ◽  
Judith Feucht ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Immunosuppressive Treatment ◽  
Calcineurin Inhibitors ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Ciclosporin A

Abstract Abstract 4542 Immunosuppressive treatment is widely used, especially after allogeneic stem cell transplantation (HSCT) to prevent or treat graft versus host disease (GvHD). Common drugs are Ciclosporin A or Tacrolimus in combination with steroids. However, immunosuppressive treatment and the underlying conditions are associated with an increased risk of viral reactivations with persistent pathogens like cytomegalovirus or adenovirus. In the absence of a protective immune response, virus infection remains a life-threatening complication after HSCT. Here we investigated the antiviral T-cell response (n=12) after ex vivo exposition with Ciclosporin A, Tacrolimus, Prednisolone or Mycophenolate at time of immunosuppression, 24 hours and 72 hours later. Analysis has been done with IFNgamma Elispot assays, confirmed by intracellular cytokine staining in flow cytometry and analysis of T-cell proliferation detected by CFSE. The antiviral T-cell response is suppressed after 24 hours using normal serum concentrations (100-200ng/ml) of cyclosporine A. T-cell annergy, induced by cyclosporine, could be reversible, after 72 without immunosuppression. Tacrolimus has a stronger immunosuppressive effect on T-cell activation within the same time and even low levels of 1ng/ml induce T-cell suppression after 72 hours. Peak levels of calcineurin inhibitors even suppressed the T-cell response to superantigens like staphylococcal antigen B or PHA. As expected, Prednisolone had a short and dose dependend effect on T-cell activation. Mycophenolate has a mild effect on the activation of virus-specific T-cells. However, all three drugs induced a significant reduction in Ag-specific T-cell proliferation. In conclusion, Interferonγ detection in virus-specific T-cells is a good diagnostic tool for clinicians to monitor the risk of viral complications in immunosuppressed patients. Tacrolimus, Cyclosporin A, Prednisolone and Mycophenolate induce an activation defect in Ag-specific T-cells with decreasing severity. The effect is reversible and corresponds to high or low serum levels. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8+T Cells To Protect against Histoplasmosis

2011 ◽  
Vol 79 (11) ◽  
pp. 4493-4502 ◽  
Author(s):  
Shih-Hung Hsieh ◽  
Jr-Shiuan Lin ◽  
Juin-Hua Huang ◽  
Shang-Yang Wu ◽  
Ching-Liang Chu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Histoplasma Capsulatum ◽  
T Cell Response ◽  
Content Type

ABSTRACTWe have previously revealed the protective role of CD8+T cells in host defense againstHistoplasma capsulatumin animals with CD4+T cell deficiency and demonstrated that sensitized CD8+T cells are restimulatedin vitroby dendritic cells that have ingested apoptotic macrophage-associatedHistoplasmaantigen. Here we show that immunization with apoptotic phagocytes containing heat-killedHistoplasmaefficiently activated functional CD8+T cells whose contribution was equal to that of CD4+T cells in protection againstHistoplasmachallenge. Inhibition of macrophage apoptosis due to inducible nitric oxide synthase (iNOS) deficiency or by caspase inhibitor treatment dampened the CD8+T cell but not the CD4+T cell response to pulmonaryHistoplasmainfection. In mice subcutaneously immunized with viableHistoplasmayeasts whose CD8+T cells are protective againstHistoplasmachallenge, there was heavy granulocyte and macrophage infiltration and the infiltrating cells became apoptotic. In mice subcutaneously immunized with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled apoptotic macrophages containing heat-killedHistoplasma, the CFSE-labeled macrophage material was found to localize within dendritic cells in the draining lymph node. Moreover, depleting dendritic cells in immunized CD11c-DTR mice significantly reduced CD8+T cell activation. Taken together, our results revealed that phagocyte apoptosis in theHistoplasma-infected host is associated with CD8+T cell activation and that immunization with apoptotic phagocytes containing heat-killedHistoplasmaefficiently evokes a protective CD8+T cell response. These results suggest that employing apoptotic phagocytes as antigen donor cells is a viable approach for the development of efficacious vaccines to elicit strong CD8+T cell as well as CD4+T cell responses toHistoplasmainfection.

Responding naive T cells differ in their sensitivity to Fas engagement: early death of many T cells is compensated by costimulation of surviving T cells

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4022-4028 ◽  
Author(s):  
Mikael Maksimow ◽  
Minna Santanen ◽  
Sirpa Jalkanen ◽  
Arno Hänninen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Early Death ◽  
T Cell Response ◽  
Naive T Cells ◽  
Naïve T Cells

Abstract Engagement of Fas (CD95) induces death of activated T cells but can also potentiate T-cell response to CD3 ligation. Yet, the effects of Fas-mediated signals on activation of naive T cells have remained controversial. We followed naive T cells responding under Fas ligation. Ligation of Fas simultaneously with activation by antigen-bearing dendritic cells promoted early death in half of the responding naive murine CD4 T cells. Surprisingly, it simultaneously accelerated cell division and interferon-γ (IFN-γ) production among surviving T cells. These cells developed quickly an activation-associated phenotype (CD44hi, CD62Llo), responded vigorously to antigen rechallenge, were partially resistant to subsequent induction of cell death via Fas, and were long-lived in vivo. Compared with cells becoming apoptotic, the surviving cells expressed lower levels of Fas and higher levels of T-cell receptor (TCR), CD4, and interleukin-2 receptor (IL-2R). Their survival was associated with expression of antiapoptotic cellular FLICE-inhibitory protein (c-FLIP), Bcl-XL, and Bcl-2. Thus, at the time of T-cell activation there is a subtle balance in the effects of Fas ligation that differs on a cell-to-cell basis. Factors that predict cell survival include expression levels of Fas, TCR, CD4, and IL-2R. Early death of some cells and a pronounced response of the surviving cells suggest that Fas ligation can both up- and down-regulate a primary T-cell response.

scholarly journals CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+ T cell response

2013 ◽  
Vol 210 (8) ◽  
pp. 1603-1619 ◽  
Author(s):  
Marc Martínez-Llordella ◽  
Jonathan H. Esensten ◽  
Samantha L. Bailey-Bucktrout ◽  
Robert H. Lipsky ◽  
Ann Marini ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Critical Role ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Functions

During the initial hours after activation, CD4+ T cells experience profound changes in gene expression. Co-stimulation via the CD28 receptor is required for efficient activation of naive T cells. However, the transcriptional consequences of CD28 co-stimulation are not completely understood. We performed expression microarray analysis to elucidate the effects of CD28 signals on the transcriptome of activated T cells. We show that the transcription factor DEC1 is highly induced in a CD28-dependent manner upon T cell activation, is involved in essential CD4+ effector T cell functions, and participates in the transcriptional regulation of several T cell activation pathways, including a large group of CD28-regulated genes. Antigen-specific, DEC1-deficient CD4+ T cells have cell-intrinsic defects in survival and proliferation. Furthermore, we found that DEC1 is required for the development of experimental autoimmune encephalomyelitis because of its critical role in the production of the proinflammatory cytokines GM-CSF, IFN-γ, and IL-2. Thus, we identify DEC1 as a critical transcriptional mediator in the activation of naive CD4+ T cells that is required for the development of a T cell–mediated autoimmune disease.

scholarly journals The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways

2019 ◽  
Vol 116 (40) ◽  
pp. 20077-20086 ◽  
Author(s):  
Chloé C. Nobis ◽  
Geneviève Dubeau Laramée ◽  
Laura Kervezee ◽  
Dave Maurice De Sousa ◽  
Nathalie Labrecque ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Time Of Day ◽  
T Cell Response

Circadian variations of various aspects of the immune system have been described. However, the circadian control of T cells has been relatively unexplored. Here, we investigated the role of circadian clocks in regulating CD8 T cell response to antigen presentation by dendritic cells (DCs). The in vivo CD8 T cell response following vaccination with DCs loaded with the OVA257–264 peptide antigen (DC-OVA) leads to a higher expansion of OVA-specific T cells in response to vaccination done in the middle of the day, compared to other time points. This rhythm was dampened when DCs deficient for the essential clock gene Bmal1 were used and abolished in mice with a CD8 T cell-specific Bmal1 deletion. Thus, we assessed the circadian transcriptome of CD8 T cells and found an enrichment in the daytime of genes and pathways involved in T cell activation. Based on this, we investigated early T cell activation events. Three days postvaccination, we found higher T cell activation markers and related signaling pathways (including IRF4, mTOR, and AKT) after a vaccination done during the middle of the day compared to the middle of the night. Finally, the functional impact of the stronger daytime response was shown by a more efficient response to a bacterial challenge at this time of day. Altogether, these results suggest that the clock of CD8 T cells modulates the response to vaccination by shaping the transcriptional program of these cells and making them more prone to strong and efficient activation and proliferation according to the time of day.

scholarly journals CD38: T Cell Immuno-Metabolic Modulator

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1716
Author(s):  
Anwesha Kar ◽  
Shikhar Mehrotra ◽  
Shilpak Chatterjee
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Metabolic Pathways ◽  
Cell Activation ◽  
T Cell Response ◽  
Nad Glycohydrolase ◽  
Profound Influence

Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells with a discrete metabolic and transcriptional feature. Compelling studies indicate that intracellular nicotinamide adenine dinucleotide (NAD+) levels have profound influence on diverse signaling and metabolic pathways of T cells, and hence dictate their functional fate. CD38, a major mammalian NAD+ glycohydrolase (NADase), expresses on T cells following activation and appears to be an essential modulator of intracellular NAD+ levels. The enzymatic activity of CD38 in the process of generating the second messenger cADPR utilizes intracellular NAD+, and thus limits its availability to different NAD+ consuming enzymes (PARP, ART, and sirtuins) inside the cells. The present review discusses how the CD38-NAD+ axis affects T cell activation and differentiation through interfering with their signaling and metabolic processes. We also describe the pivotal role of the CD38-NAD+ axis in influencing the chromatin remodeling and rewiring T cell response. Overall, this review emphasizes the crucial contribution of the CD38−NAD+ axis in altering T cell response in various pathophysiological conditions.

scholarly journals γδT Cells Are Required for CD8+ T Cell Response to Vaccinia Viral Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Dai ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Critical Role ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Γδt Cells

Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+ T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+ T cell response to VV infection. In this study, we showed that γδT cells play an important role in promoting CD8+ T cell response to VV infection. We found that γδT cells can directly present viral antigens in the context of MHC-I for CD8+ T cell activation to VV in vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in γδT cells is required for activation of γδT cells and CD8+ T cells. These results illustrate a critical role for γδT cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of γδT cells.

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