New Insights on OX40 in the Control of T Cell Immunity and Immune Tolerance In Vivo

Abstract

OX40 is a T cell costimulatory molecule that belongs to the TNFR superfamily. In the absence of immune activation, OX40 is selectively expressed by Foxp3+ Tregs, but not by resting conventional T cells. The exact role of OX40 in Treg homeostasis and function remains incompletely defined. Here, we demonstrate that OX40 engagement in vivo in naïve mice induces initial expansion of Foxp3+ Tregs, but the expanded Tregs have poor suppressive function and exhibit features of exhaustion. We also show that OX40 enables the activation of the Akt and Stat5 pathways in Tregs, resulting in transient proliferation of Tregs and reduced levels of Foxp3 expression. This creates a state of relative IL-2 deficiency in naïve mice that further impacts Tregs. This exhausted Treg phenotype can be prevented by exogenous IL-2, as both OX40 and IL-2 agonists drive further expansion of Tregs in vivo. Importantly, Tregs expanded by both OX40 and IL-2 agonists are potent suppressor cells, and in a heart transplant model, they promote long-term allograft survival. Our data uncover a novel role for OX40 in promoting immune tolerance and may have important clinical implications.

Effector T Cells Boost Regulatory T Cell Expansion by IL-2, TNF, OX40, and Plasmacytoid Dendritic Cells Depending on the Immune Context

“…Our data are in line with the ones of Oppenheim and colleagues (19,20), which showed a direct effect of TNF on Treg cells via its TNFR2, inducing an increase of their proliferation and survival. Regarding OX40, it has been shown that OX40 agonist administration in- The Journal of Immunologyduced an increase of Treg cell proliferation and that OX40-deficient Treg cells had reduced survival capacity in inflamed tissues (33,34). Interestingly, blocking both TNF and OX40L in ins-HA mice did not fully inhibit the Teff→Treg boost (data not shown), suggesting that other molecules were involved.…”

The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice

“…Notably, our findings share similarities with other studies using Ox40 agonist treatments. Ox40 agonist treatment exacerbated models of experimental uveitis (67,68) and promoted inflammatory lung pathology in B6 mice (69). However, in other models, the diseasepromoting effects of Ox40 agonism depended upon age and disease severity of the animals (e.g., in experimental autoimmune encephalitis and type 1 diabetes, in which treatment promoted disease during later or effector phases but protected from disease when provided during early or priming phases) (70)(71)(72).…”

Cloning, Expression, and Functional Characterization of TL1A-Ig

“…Unlike 4C12, the fusion protein induced the proliferation of CD4 + Foxp3 + Tregs in vitro and could be repeatedly administered to maintain elevated Treg levels in vivo. Although there have been studies reporting methods that expand endogenous Tregs (22)(23)(24), to our knowledge we provide the first description of a molecule and method to sustain prolonged in vivo Treg expansion. The TL1A-Ig fusion protein may provide both ex vivo and in vivo strategies for Tregbased therapies in humans.…”