T cell anergy is a tolerant state that the lymphocyte is intrinsically unresponsive following prior exposure to an antigen, but remains alive for an extended period of time (Schwartz, 2003). T cell anergy can be prevented by costimulatory signals provided by accessory molecules like CD28 or the interleukin 2 receptor (IL-2R) in vitro. CTLA-4 also plays a role for CD4+ T cell anergy induction, as blockage of CTLA-4 pathway by blocking mAb or using CTLA-4-/- T cells can prevent the T cell anergy induction in vivo (Greenwald et al., 2001; Perez et al., 1997). Recentreports showed that T cell clonal anergy could be prevented by CD40 or 0X40 mAb stimulation, highlighting the role of co-signaling molecules in the regulation of T cell anergy (Bansal-Pakala et al., 2001; Diehl et al., 1999). Importantly, the provision of 0X40 signaling by agonist mAb could reverse established T cell anergy in vivo. Recent studies from our lab demonstrate an important role of CD137 in the regulation of CD8+ T cell anergy. The effect of CD137 agonist mAb in the prevention and reversal of CD8+ T cell tolerance was evaluated in three independent systems in vivo (Wilcox et al., 2004).
In the OT-1 system, soluble chicken ovalbumin (OVA) peptide encoding an H-2Kb-restricted epitope was infused intravenously (i.v.) into the mice carrying OT-1 TCR transgenic T cells. A high dose OVA peptide injection led to express VLA-4 on nearly all OT-1 cells, indicating unexceptional antigen exposure of OT-1 cells in this system. Ten days after peptide injection, while the majority of activated OT-1 cells underwent contraction, a significant number of OT-1 cells persisted and was unresponsive to OVA rechallenge both in vitro and vivo, suggesting induction of OVA-specific T cell anergy. Administration of anti-CD137 mAb together with OVA peptide led to about ten-fold increase of OT-1 cells compared with the mice injected with peptide alone. Furthermore, in contrast to the rapid declining of effector OT-1 cells in control mice, the mice receiving anti-CD137 mAb did not have a clear contraction phase, leading to the persistence of a large number of OT-1 cells at least three weeks. Upon restimulation, the OT-1 cells from CD137 mAb treated group proliferated vigorously and produced large amount of IL-2. The level of proliferation and IL-2 secreting was significantly higher than naive OT-1 cells from PBS treated group, indicating that CD137 stimulation prevents anergy induction and therefore promotes memory T cell development. More importantly, CD137 mAb together with antigen also reverse established T cell anergy. When CD137 mAb together with OVA peptide was administered into mice containing pre-established anergic OT-1 cells 10 days earlier, a massive expansion of OT-1 cells was induced. These proliferating OT-1 cells expressed activation markers and regained antigen-specific cytotoxicity.
Infusion of P1A peptide, which encodes a CD8+ T cell epitope for a dominant tumor antigen of P815 mastocytoma, could induce T cell tolerance and lead to growth of a regressive P815 clone (P815R) in syngeneic DBA/2 mice. The provision of anti-CD137 mAb together with P1A peptide prevented tumor growth, suggesting that CD137 stimulation could prevent the P1A peptide from induction of tolerance. Furthermore, even 13 days after peptide infusion, when tumor tolerance was already established, the injection of anti-CD137 mAb could still lead to tumor regression. While these data strongly support a potential role of CD137 signaling in reversal of T cell anergy, the possibility that CD137 stimulation increases anti-tumor response by broadening T cell recognition against subdominant epitopes cannot be excluded.
In a bone marrow chimera model, 2C transgenic T cell, which recognizes H-2Ld alloantigen, was cotransferred with bone marrow into lethally irradiated BDF1 mice. The persistence of host antigens could lead to completely anergy of 2C. As a result, the persistent 2C T cells were unresponsive to stimulation by TCR cross-linking and could not lyse any transferred CFSE-labeled target cells. However, co-infusion of anti-CD137 mAb reversed the anergy state of 2C T cell, leading to the increased number of 2C T cell in the host, together with a marked reduction of transferred target cells.
Additional evidence from other labs also supports the role of CD137 signal in the regulation of T cell anergy. In vivo triggering of CD137 by mAb could prevent the induction of peptide-specific tolerance, and result in the priming of a potent cytotoxic T lymphocytes (CTL) response instead. Furthermore, injection of anti-CD137 mAb could work as effectively as anti-CD40 mAb, replacing the need for CD4+ T cell help in the cross-priming of tumor-specific CTL immunity (Diehl et al, 2002). Similar to CD8+ T cells, peptide-induced CD4+ T cell tolerance could also be prevented by CD137 engagement during priming (Bansal-Pakala and Croft, 2002).
In summary, these studies established a new function of CD137 signaling in preventing and/or breaking CD8+ T cell anergy. The effect is antigen-specific since at least breaking anergy requires co-administration of antigen. As tumor growth or chronic viral infection often induce T cell anergy, these findings provide a new approach for therapies.
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