The concept of suppressor T cells exits for decades as a mechanism for the regulation of peripheral tolerance, though the molecular evidence for this phenomenon is largely unknown. During the last ten years, the identification of CD4+CD25+ cells as a suppressor T cell subtype by Sakaguchi and colleagues have triggered explosive growth of knowledge in this field (Sakaguchi, 2004). In normal mice, approximately 10% of CD4+ T cells express CD25. These cells are anergic when stimulated via their TCR but can proliferate in presence of IL-2. CD4+CD25+ cells can inhibit a variety of types of immune responses, both in culture and in vivo. The development of CD4+CD25+ seems to be IL-2-dependent and requires endogenous B7-CD28 interaction, as the absence of IL-2, IL-2R, CD80/CD86, or CD28 results in a dramatic reduction of Treg number in peripheral lymphoid tissues (Bluestone and Abbas, 2003). Besides CD25, Foxp3, a Forkhead family transcriptional factor, is emerging as a promising signature for Treg, as recent studies have shown that the majority of Treg cells express Foxp3 and trans-fection of CD4+CD25- T cells with Foxp3 confers regulatory activity (Fontenot et al., 2003; Hori et al., 2003; Khattri et al., 2003). Treg cells also constitutively express high-level of costimulatory molecules cytotoxic T lymphocyte-associated antigen (CTLA)-4, which has been shown to functionally inhibit immune response by initiating tryptophan catabolism in dendritic cells by binding to B7-1 and/or B7-2 (Fallarino et al., 2003). Recently gene array analyses have shown that several tumor necrosis factor (TNF) family members including CD137 were highly expressed in CD4+CD25+ cells, which was confirmed by surface staining (Gavin etal., 2002; McHugh etal., 2002). The functions ofCD137 on Treg was conducted by several independent groups both in vitro and in vivo. Although the results from different labs were sharply different, all data support a role of CD137 in the regulation of Treg cell functions.
Choi et al. found that freshly isolated CD4+CD25+ T cells constitutively express low-level CD137 and its expression upregulated upon activation (Choi et al., 2004). As CD4+CD25+ Treg from CD137-/- mice suppressed responder T cells to the same extent as wild-type Treg do, CD137 did not appear to be a key player in the contact-dependent suppressor activity of Treg cells. However, signaling through CD137 on CD4+CD25+ cells could neutralize the suppressive effect of Treg cells, although it did not affect Treg cell proliferation. When CD25- cells from CD137-/- mice were co-cultured with pre-activated CD25+ Treg cells, the presence of agonistic CD137 mAb efficiently antagonized the suppressive activity of Treg cells. However, CD137 stimulation could reverse the suppression of naive CD25+ Treg cells only in the presence of exogenous IL-2. Differential expression level of CD137 on naive versus activated Treg could be a possible explanation, as enough CD137 signaling is required to disrupt the suppressive effect of Treg cells. It should be noted that CD137 signals on Treg was transient, as Treg cells regained their suppressive ability upon removal of CD137 stimulation. In vivo GVHD experiments also supported that CD137 signals inhibit the suppressive activity of Treg cells: The co-transfering of CD25+ Treg cells together with purified CD25-CD4+ cells into MHC-mismatched, sublethally irradiated recipients significantly delayed death from GVHD. Co-injection of CD137 agonist mAbs neutralized Treg-mediated suppression and accelerated death, even when the CD25- T cells were from CD137 deficient mice, supporting a direct role of CD137 signal on Treg. Interestingly, when CD25- T cells from wild type mice co-cultured with CD25+ Treg from CD137- deficient mice, CD137 signaling also abrogated Treg-mediated suppression, implying that CD137 stimulation renders CD25- T cells resistant to regulatory T cell-mediated suppression.
Consistent to these findings, Morris et al., also found that CD137 signaling interferes with CD4+CD25+ Treg-mediated tolerance in an experimental autoimmune thyroiditis (EAT) mouse model (Morris et al., 2003). In vivo depletion of CD25+ cells could abrogate established tolerance, indicating that CD4+CD25+ Treg cells are essential for the tolerance induction. Administration of CD137 mAb inhibited the tolerance induction and interfered with the established tolerance to EAT. In vitro CD137 signals also inhibited the suppression of mouse thyroglobulin-specific T cell proliferation by CD4+CD25+ Treg cells. In addition, CD137 stimulation did not increase Treg cells to proliferate. Thus, the authors suggested that signaling through CD137 on the autoreactive T cells directly overcomes suppression by CD4+CD25+ Treg cells.
In sharp contrast, Zheng et al. (2004) found that CD137 signal was a strong costimulator for CD4+CD25+ cells both in vitro and vivo instead. Purified CD4+CD25+ Treg cells proliferate actively in the presence of CD137L-Fc (both soluble and cross-linked by an Fc receptor). No detectable IL-2 was produced during Treg proliferation, suggesting that IL-2 did not involve in this process. Furthermore, the expanded Treg cells by CD137 retained their suppressive function. Although there is no straightforward answer for these seemly contradictory observations, it is not a total surprise in the context of previous observation that a CD137 signal can be either suppressive or stimulatory for CD4+ T cells. Further validation for these findings will be needed in the future.
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