There is ample evidence that CD137 signal plays an important role in costim-ulation of T cell activation in the presence of T cell receptor (TCR) signal in vitro. Cross-linking of CD137 by anti-CD137 antibody resulted in an enhancement of purified splenic T cell proliferation compared to that stimulated by anti-CD3 alone (Pollok et al., 1993). Similarly, CD137 engagement by immobilized CD137L fusion protein or CD137L transfectants augmented the T cell proliferation and cytokine production (Goodwin et al., 1993; DeBenedette et al., 1995). A soluble CD137 protein (CD137Fc) could significantly inhibit T cell proliferation and IL-2 production in both a culture of anti-CD3 stimulated splenocytes and primary mixed leukocyte reaction (MLR) (Hurtado etal., 1995). CD137Ltransfectant could costimulateCD28-deficientT cells, suggesting that CD137L/CD137 interaction represents a costimulatory pathway independent of CD28 (DeBenedette et al., 1997). Similarto CD28, CD137 engagement promotes T cell proliferation and IL-2
Yuwen Zhu and Lieping Chen • Department of Dermatology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
CD137 Pathway: Immunology and Diseases. Edited by Lieping Chen, Springer, New York, 2006
production by enhancing cell division. Furthermore, CD137 is believed to play a more important role in preventing activation induced cell death (AICD) (Lee et al., 2002; Takahashi et al., 1999). CD137 engagement was shown to increase expression of the antiapoptotic genes bcl-x(L), bfl-1 and c-FLIP via CD137-mediated phosphatidylinositol 3-kinase, the AKT/protein kinase B and/or NF-kappa B activation (Starck et al., 2005).
Similar to mouse T cells, cross-linking of CD137 costimulates both CD4+ and CD8+ T cells in humans. Both monoclonal antibodies to human CD137 and cells transfected with human CD137 ligand induced a strong proliferative response in mitogen co-stimulated primary T cell response (Alderson et al., 1994). The presence of CD137L on the APC led to increased cell expansion, cytokine production, and the development of cytolytic effector function by human T cells (Bukczynski et al., 2003). CTLA-4 Ig partially blocked CD137L-dependent IL-2 production, suggesting CD28 signaling pathway may partially overlap with that of CD137. On the other hand, when cocultured with tumor cells expressing human CD137L in the presence of CD3 antibody, CD28-T cells freshly isolated from peripheral blood mononuclear cells (PBMC) clearly enhanced their proliferation, effector function as well as the expression of anti-apoptotic protein Bcl-XL, implying a CD28-independent costimulatory role of CD137 in human T cells (Wen et al., 2002). Reduced apoptosis is observed after co-stimulation by CD137 engagement, consistent with the increased levels of Bcl-x (L) in CD137 antibody-treated CD8+ T cells (Laderach et al., 2002). In addition, artificial antigen-presenting cells (APC) co-expressing ligands for CD28 and CD137 synergistically improved T cell proliferation and survival, compared with CD28 alone (Maus et al., 2002). All together, the data in humans suggest that CD137 signal contributes to the human T cell proliferation and effector T cell differentiation, and manipulation of CD137 signaling could be an effective tool to promote immune response in the aged or chronically infected individuals where CD28-T cells accumulate.
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