OX40 costimulation and regulatory T cells

Immune regulation is central to T-cell responses and the acquisition of tolerance. A subset of CD4⁺CD25⁺ T cells that are highly specialized in regulatory functions expresses a transcription factor, Foxp3; the cells comprising this subset are called Foxp3⁺ Tregs. Such Foxp3⁺ Tregs are dedicated to the creation and maintenance of immune tolerance by controlling cytopathic effector T cells.¹  Phenotypically, activated effector T cells and Foxp3⁺ Tregs express a plethora of cell-surface receptors, some of which are identical on both subsets (see the figure). Thus, a better appreciation of how the same receptors regulate functionally divergent T-cell subsets is an important and clinically relevant issue.

OX40 (CD134) is one such cell-surface receptor that can be expressed by both effector T cells and Tregs.²  Although OX40, a member of the TNF/TNF-R superfamily, has been extensively studied as a potent costimulatory molecule to activated effector T cells,³  its putative role in regulating Treg function remains to be elucidated. In the current issue of Blood, Vu and colleagues detail a surprising finding: that OX40 plays a dual role in the T-cell response, and may inhibit and negatively regulate Foxp3⁺ Tregs. In a series of well-designed and elegant experiments using a newly developed Foxp3-GFP reporter model, the authors discovered that Foxp3⁺ Tregs are present in normal numbers in OX40-deficient mice and, when selected and tested in vitro, they do function just as well as WT Foxp3⁺ Tregs in suppressing effector T-cell activation. Thus, both development and function of Foxp3⁺ Tregs appear to be OX40 independent. Interestingly, stimulation of OX40 on mature Foxp3⁺ Tregs completely abolished the ability of Tregs to suppress effector T-cell proliferation and cytokine production. Moreover, OX40 signaling to Tregs does not seem to affect their survival and proliferation, but appears to repress the expression of Foxp3, which is a striking feature of this model. Importantly, the induction of Foxp3 expression in freshly activated effector T cells by TGF-β was consistently prevented by OX40. Thus, OX40 represents a potent negative regulator not only to natural Foxp3⁺ Tregs but also to Tregs generated de novo from activated effector T cells, suggesting that OX40 controls an important checkpoint in Treg homeostasis.

The findings of Vu and colleagues imply that, unlike other costimulatory molecules, OX40 plays a dual role in T-cell activation. It is undoubtedly a potent costimulatory molecule to effector T cells, but it is also a powerful negative regulator of Foxp3⁺ Tregs. Indeed, OX40 signaling has been recently shown to shut off IL-10–producing CD4⁺ type 1 regulatory T (Tr1) cells.⁴  However, many questions remain to be addressed. Clearly, OX40 can disarm Foxp3⁺ Tregs, but it remains unclear whether this effect is reversible or permanent. In addition, the phenotype and function of effector T cells that are supposed to become new Foxp3⁺ Tregs but are prevented by OX40 require careful investigation. Given the close relationship between inducible Tregs and Th17 cells,⁵  the possibility of Th17 induction by OX40 needs to be examined. Finally, the molecular fingerprints as to how OX40 signals functionally different effector T cells and Foxp3⁺ Tregs need to be established. Nonetheless, the findings of Vu and colleagues are significant and may have far-reaching clinical ramifications, as manipulation of Foxp3⁺ Tregs is clearly an attractive approach in transplantation tolerance, autoimmunity, and cancer treatment.