Limits...
4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.

Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW, Brown TJ, Emswiler J, Raecho H, Larsen CP, Pearson TC, Ledbetter JA, Aruffo A, Mittler RS - J. Exp. Med. (1997)

Bottom Line: Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB.In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice.The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.

ABSTRACT
The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-gamma production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

Show MeSH

Related in: MedlinePlus

Costimulation of CD8+ T cells with anti-4-1BB but not anti-CD28 leads to IFN-γ production. Unseparated and CD4+ or CD8+ resting T  cells were stimulated with anti-CD3 (•) or anti-CD3 and either anti-CD28 (▪) or the anti–4-1BB mAb 3H3 (▴). Activated T cell culture SN were collected at 24, 48, 72, and 96 h and assayed by ELISA for IL-2, IL-4, IL-10, and IFN-γ.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2198949&req=5

Figure 7: Costimulation of CD8+ T cells with anti-4-1BB but not anti-CD28 leads to IFN-γ production. Unseparated and CD4+ or CD8+ resting T cells were stimulated with anti-CD3 (•) or anti-CD3 and either anti-CD28 (▪) or the anti–4-1BB mAb 3H3 (▴). Activated T cell culture SN were collected at 24, 48, 72, and 96 h and assayed by ELISA for IL-2, IL-4, IL-10, and IFN-γ.

Mentions: To understand better how 4-1BB–mediated signals amplify CTL activity, we analyzed the kinetics of IL-2, IL-4, IL-10, and IFN-γ production by resting CD4+ and CD8+ or unseparated T cells stimulated with anti-CD3 or anti-CD3 together with anti-CD28 or anti–4-1BB. In Fig. 7, it can be seen that CD28-mediated costimulation significantly amplified the production of all four lymphokines by CD4+ and unseparated T cells but had little effect on CD8+ T cells. In contrast, 4-1BB–mediated costimulation had no significant effect upon the CD4+ T cell subset with perhaps IFN-γ being the exception. On the other hand, 4-1BB–mediated costimulation markedly enhanced the production of IFN-γ by CD8+ T cells as well as in unseparated T cells. This feature appeared to be a general characteristic of anti–4-1BB mAbs, as several of them were tested and found to have the same properties (data not shown).


4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.

Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW, Brown TJ, Emswiler J, Raecho H, Larsen CP, Pearson TC, Ledbetter JA, Aruffo A, Mittler RS - J. Exp. Med. (1997)

Costimulation of CD8+ T cells with anti-4-1BB but not anti-CD28 leads to IFN-γ production. Unseparated and CD4+ or CD8+ resting T  cells were stimulated with anti-CD3 (•) or anti-CD3 and either anti-CD28 (▪) or the anti–4-1BB mAb 3H3 (▴). Activated T cell culture SN were collected at 24, 48, 72, and 96 h and assayed by ELISA for IL-2, IL-4, IL-10, and IFN-γ.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198949&req=5

Figure 7: Costimulation of CD8+ T cells with anti-4-1BB but not anti-CD28 leads to IFN-γ production. Unseparated and CD4+ or CD8+ resting T cells were stimulated with anti-CD3 (•) or anti-CD3 and either anti-CD28 (▪) or the anti–4-1BB mAb 3H3 (▴). Activated T cell culture SN were collected at 24, 48, 72, and 96 h and assayed by ELISA for IL-2, IL-4, IL-10, and IFN-γ.
Mentions: To understand better how 4-1BB–mediated signals amplify CTL activity, we analyzed the kinetics of IL-2, IL-4, IL-10, and IFN-γ production by resting CD4+ and CD8+ or unseparated T cells stimulated with anti-CD3 or anti-CD3 together with anti-CD28 or anti–4-1BB. In Fig. 7, it can be seen that CD28-mediated costimulation significantly amplified the production of all four lymphokines by CD4+ and unseparated T cells but had little effect on CD8+ T cells. In contrast, 4-1BB–mediated costimulation had no significant effect upon the CD4+ T cell subset with perhaps IFN-γ being the exception. On the other hand, 4-1BB–mediated costimulation markedly enhanced the production of IFN-γ by CD8+ T cells as well as in unseparated T cells. This feature appeared to be a general characteristic of anti–4-1BB mAbs, as several of them were tested and found to have the same properties (data not shown).

Bottom Line: Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB.In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice.The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.

ABSTRACT
The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-gamma production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

Show MeSH
Related in: MedlinePlus