Distinct Roles for the OX40-OX40 Ligand Interaction in Regulatory and Nonregulatory T Cells

Abstract

The OX40 (CD134) molecule is induced primarily during T cell activation and, as we show in this study, is also expressed on CD25+CD4+ regulatory T (Treg) cells. A necessary role for OX40 in the development and homeostasis of Treg cells can be inferred from the reduced numbers of the cells present in the spleens of OX40-deficient mice, and their elevated numbers in the spleens of mice that overexpress the OX40 ligand (OX40L). The homeostatic proliferation of Treg cells following transfer into lymphopenic mice was also found to be potentiated by the OX40-OX40L interaction. Suppression of T cell responses by Treg cells was significantly impaired in the absence of OX40, indicating that, in addition to its homeostatic functions, OX40 contributes to efficient Treg-mediated suppression. However, despite this, we found that CD25−CD4+ T cells became insensitive to Treg-mediated suppression when they were exposed to OX40L-expressing cells, or when they were treated with an agonistic OX40-specific mAb. OX40 signaling could also abrogate the disease-preventing activity of Treg cells in an experimental model of inflammatory bowel disease. Thus, although the data reveal important roles for OX40 signaling in Treg cell development, homeostasis, and suppressive activity, they also show that OX40 signals can oppose Treg-mediated suppression when they are delivered directly to Ag-engaged naive T cells.

Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

“…In summary, our results clearly demonstrate that gut-specific fast homeostatic proliferation plays a critical role in inducing guthoming a 4 b 7 + IL-17A + T cells, which is dependent on OX40 signals. Although the systemic inhibition of OX40 signals, either in OX40L-knockout mice or by treatment with an anti-OX40L mAb, drastically ameliorates several types of IBDs and GVHD (34,35,61), our study revealed that the OX40-OX40L interactions necessary for generating intestinal Th17 cells may occur in the MLNs. Therefore, it may be possible to develop therapeutic strategies for IBDs and GVHD by controlling the OX40-OX40L interactions in MLNs.…”

“…In particular, both commensal bacteria and OX40 are required for fast proliferation in MLNs and for guttropic T cell accumulation in the lamina propria of the intestine. Studies in several animal models have demonstrated that OX40-OX40L interactions mediate the development of IBDs and GVHD, both of which are pathogenically associated with the homeostatic proliferation of CD4 + T N cells (34,35,61). Therefore, it is likely that a 4 b 7 + Th17 cells generated through fast homeostatic proliferation in MLNs are also involved in the pathogenesis of these diseases in an OX40-dependent manner.…”

“…The in vivo blockade of T cell costimulatory signals mediated through OX40, which belongs to the TNF receptor superfamily, improves experimental colitis by suppressing the homeostatic proliferation of pathogenic CD4 + T cells (34,35). Therefore, we examined OX40 expressed on donor T cells in MLNs during homeostatic proliferation and found OX40 on fast-but not slowproliferating cells (Fig.…”

“…Ly5.2 + C57BL/6 mice between 6 and 8 wk of age were purchased from Japan SLC (Hamamatsu, Japan); Ly5.1 + C57BL/6 mice have been described previously (35). Aly/aly mice were purchased from CLEA Japan (Tokyo, Japan).…”

“…This systemic proliferative response contributes not only to maintenance of T cell homeostasis (2, 4) but also to pathogenesis for inflammatory diseases including IBDs and GVHD (32)(33)(34)(35). The systemic homeostatic proliferation has been studied by transferring T cells into lymphopenic hosts, such as sublethally irradiated or Rag-deficient mice, and examining division and differentiation of donor cells in the spleen and/ or cutaneous lymph nodes (36)(37)(38)(39).…”