scholarly journals Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Can Regulate Dendritic Cell–induced Activation and Cytotoxicity of CD8+ T Cells Independently of CD4+T Cell Help

1999 ◽  
Vol 189 (7) ◽  
pp. 1157-1162 ◽  
Author(s):  
Kathy D. McCoy ◽  
Ian F. Hermans ◽  
J. Henry Fraser ◽  
Graham Le Gros ◽  
Franca Ronchese
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cd4 T Cell ◽  
Cd4 T Cell Help ◽  
T Cell Help

The mechanisms that regulate the strength and duration of CD8+ cytotoxic T cell activity determine the effectiveness of an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8+ T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8+ T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti–CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8+ T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4+ T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8+ T cells, indicating its potential for tumor immunotherapy even in situations in which CD4+ T cell help is limited or absent.

scholarly journals CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Yu-Jung Lu ◽  
Palmira Barreira-Silva ◽  
Shayla Boyce ◽  
Jennifer Powers ◽  
Kelly Cavallo ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Cd4 T Cell Help ◽  
T Cell Help

SummaryCD4 T cells are essential for immunity to tuberculosis because they produce cytokines including interferon-γ. Whether CD4 T cells act as “helper” cells to promote optimal CD8 T cell responses during Mycobacterium tuberculosis is unknown. Using two independent models, we show that CD4 T cell help enhances CD8 effector functions and prevents CD8 T cell exhaustion. We demonstrate synergy between CD4 and CD8 T cells in promoting the survival of infected mice. Purified helped, but not helpless, CD8 T cells efficiently restrict intracellular bacterial growth in vitro. Thus, CD4 T cell help plays an essential role in generating protective CD8 T cell responses against M. tuberculosis infection in vitro and in vivo. We infer vaccines that elicit both CD4 and CD8 T cells are more likely to be successful than vaccines that elicit only CD4 or CD8 T cells.

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

scholarly journals The CD4+ T-cell help signal is transmitted from APC to CD8+ T-cells via CD27–CD70 interactions

2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Sonia Feau ◽  
Zacarias Garcia ◽  
Ramon Arens ◽  
Hideo Yagita ◽  
Jannie Borst ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cell ◽  
Cd4 T Cell Help ◽  
T Cell Help

Augmentation of Therapeutic Tumor Vaccine Efficacy by Genetic Engineering of CD4+ T Cell Help for Tumor Vaccine-Reactive CD8+ T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3175-3175
Author(s):  
Sanju Jalla ◽  
Erin McCadden ◽  
Jie Wang ◽  
Ephraim J. Fuchs ◽  
Katharine A. Whartenby
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Autologous Tumor Cell ◽  
Autologous Tumor ◽  
Tumor Bearing ◽  
Cd4 T Cell Help ◽  
T Cell Help

Abstract Since CD4+ T cell help has been proposed to be required for maintaining the activity of tumor-specific CD8+ T cells, tolerance in tumor-specific CD4+ T cells may seriously impair the efficacy of therapeutic tumor vaccines. To overcome this problem, we devised a strategy to “engineer” CD4+ T cell help by treating tumor-bearing animals with nonmyeloablative conditioning and transplantation of autologous hematopoietic stem cells (HSCs) that have been genetically modified, via lentiviral transduction, to express an antigen containing “foreign” CD4+ T cell epitopes. After hematopoietic reconstitution, animals received the combination of an autologous tumor cell vaccine and an infusion of primed CD4+ T cells specific for the expressed epitopes. Using influenza hemagglutinin (HA) as the model antigen, we first confirmed that transplantation of HA-transduced HSCs led to efficient expression of HA by antigen-presenting cells, as demonstrated by the clonal expansion of adoptively transferred, HA-specific CD4+ transgenic T cells in mice receiving HA-transduced HSCs but not in mice receiving nerve growth factor receptor (NGFR) gene-transduced HSCs. Next, BALB/c mice harboring 13 day old, metastatic 4T1 mammary cancer were treated with removal of the primary, nonmyeloablative conditioning and transplantation of HA-transduced syngeneic HSCs, and following hematopoietic reconstitution, with concomitant autologous tumor cell vaccination and adoptive transfer of in vitro activated, HA-specific transgenic CD4+ T cells. This therapy was successful in curing the majority of tumor bearing mice, and was superior to the same therapy given to mice transplanted with NGFR-transduced stem cells. Finally, we found that the anti-tumor effect of vaccination plus exogenous T cell help was abolished by the adoptive transfer of either CD4+ or CD8+ T cells from tumor-bearing mice, suggesting that tumor-bearing mice contain both potential effectors and suppressors of anti-tumor immunity, the latter of which are abolished by the non-myeloablative conditioning. These results highlight the importance of CD4+ T cell help in the induction of therapeutic anti-tumor immunity.

scholarly journals HIV-Resistant and HIV-Specific CAR-Modified CD4+ T Cells Mitigate HIV Disease Progression and Confer CD4+ T Cell Help In Vivo

2020 ◽  
Vol 28 (7) ◽  
pp. 1585-1599 ◽  
Author(s):  
Colby R. Maldini ◽  
Kevin Gayout ◽  
Rachel S. Leibman ◽  
Derrick L. Dopkin ◽  
Joshua P. Mills ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Hiv Disease ◽  
Cd4 T Cell Help ◽  
T Cell Help

scholarly journals Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection

2011 ◽  
Vol 108 (52) ◽  
pp. 21182-21187 ◽  
Author(s):  
R. D. Aubert ◽  
A. O. Kamphorst ◽  
S. Sarkar ◽  
V. Vezys ◽  
S.-J. Ha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd4 T Cell ◽  
Chronic Viral Infection ◽  
Cd4 T Cell Help ◽  
T Cell Help

scholarly journals B Cells Directly Tolerize CD8+ T Cells

1998 ◽  
Vol 188 (11) ◽  
pp. 1977-1983 ◽  
Author(s):  
Sally R.M. Bennett ◽  
Francis R. Carbone ◽  
Tracey Toy ◽  
Jacques F.A.P. Miller ◽  
William R. Heath
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
I Cells

This report investigates the response of CD8+ T cells to antigens presented by B cells. When C57BL/6 mice were injected with syngeneic B cells coated with the Kb-restricted ovalbumin (OVA) determinant OVA257–264, OVA-specific cytotoxic T lymphocyte (CTL) tolerance was observed. To investigate the mechanism of tolerance induction, in vitro–activated CD8+ T cells from the Kb-restricted, OVA-specific T cell receptor transgenic line OT-I (OT-I cells) were cultured for 15 h with antigen-bearing B cells, and their survival was determined. Antigen recognition led to the killing of the B cells and, surprisingly, to the death of a large proportion of the OT-I CTLs. T cell death involved Fas (CD95), since OT-I cells deficient in CD95 molecules showed preferential survival after recognition of antigen on B cells. To investigate the tolerance mechanism in vivo, naive OT-I T cells were adoptively transferred into normal mice, and these mice were coinjected with antigen-bearing B cells. In this case, OT-I cells proliferated transiently and were then lost from the secondary lymphoid compartment. These data provide the first demonstration that B cells can directly tolerize CD8+ T cells, and suggest that this occurs via CD95-mediated, activation-induced deletion.

Sign in / Sign up

Export Citation Format

Share Document