T lymphocytes require at least 2 signals to be activated and to differentiate into antigen-specific effector cells: signal 1 results from T-cell receptor (TCR)–dependent antigen recognition, while signal 2 is provided by cognate interactions between costimulatory receptors on T cells (such as CD28) and their corresponding ligands on antigen-presenting cells (such as CD80 and CD86). In the absence of signal 2, T cells cannot respond to the antigen that they recognize via their TCR and thus become anergic.1 Anergy is a fundamental process in T-cell biology that contributes to the functional phenotype of T-cell tolerance, with both beneficial and detrimental consequences for the organism. Consider organ transplantation as an example: here, the induction of donor-specific T-cell anergy in the transplant recipient is the ultimate goal of transplantation immunologists, and numerous approaches based on the interference with costimulatory signalling pathways have been explored.2 On the other hand, T-cell ignorance of tumor cells may allow tumors to escape immune attack. In this scenario, it would be desirable to prevent the induction of anergy, or even to reverse established tumor-induced T-cell anergy, in order to turn ignorant T cells into furious tumor-attacking cytolytic T lymphocytes (CTLs). By providing interleukin-2 or CD28 costimulation, anergy in CD4+ T cells can be prevented or reversed in vitro, and signalling through OX40 (CD134) or CD40 molecules together with TCR engagement breaks CD4+ T-cell anergy even in vivo.3 So far, however, it has not been possible to reverse established anergy in CD8+ CTLs in vivo.
Wilcox and colleagues (page 177) have now identified a novel approach to prevent, and even reverse, established anergy in CD8+ T cells by using an agonistic anti-CD137 monoclonal antibody (mAb). CD137 (4-1BB) is a member of the tumor necrosis factor–receptor (TNFR) superfamily with well-known costimulatory and cell death–preventing activity on CD8+ T cells. In their studies, Wilcox et al investigated the effect of anti-CD137 mAb in 3 murine model systems of CD8+ T-cell anergy in vivo. In the first system, anergy was induced with a tumor antigen–derived peptide, with the consequence of progressive growth of an otherwise nonprogressive regressor P815R tumor cell in the immunized mice. In the second system, anergy was induced by soluble ovalbumin peptide in mice carrying a transgenic TCR specific for the H-2Kb–restricted ovalbumin peptide. Finally, they also explored the induction of CD8+ T-cell anergy to cell-associated (as opposed to soluble) antigens in bone marrow chimeras using the bone marrow from 2C TCR transgenic mice with an H-2Ld–reactive TCR transplanted into lethally irradiated C57BL/6 × DBA/2 F1 mice. Remarkably, the infusion of the agonistic anti-CD137 mAb not only prevented the induction of anergy in the CD8+ CTLs, but, more importantly, even reversed the established anergy in all 3 instances. These impressive results suggest that triggering of the CD137 receptor by agonistic mAb might be a more general and promising principle of breaking CTL anergy in vivo. This is of special importance for tumor immunology, where the activation of tumor-reactive but sleeping CTLs by CD137 signalling definitively deserves further exploration.
From a mechanistic point of view, it is not completely clear whether the prevention and reversal of anergy results from direct triggering of CD137 on CD8+ CTLs. Alternatively, the infusion of anti-CD137 mAb might also affect other cells such as activated CD4+ T cells, natural killer (NK) cells, or dendritic cells, all of which also express CD137. Future studies will investigate these issues and, more importantly, will address whether this approach carries the potential of successful translation into clinical application. Finally, we should keep in mind that nonreactivity at the T-cell level is more than just “anergy.” While “suppressor cells” had been deleted from the immunologic vocabulary for 2 decades, their recent resurrection as “regulatory T cells” reminds us that immunologic tolerance involves multiple and nonexclusive principles. In this regard, it will be of interest to consider the possible interplay between CD137 triggering and the action of regulatory T cells.
