Immune regulation and control of regulatory T cells by OX40 and 4-1BB

Abstract

The TNFR family members OX40 (CD134) and 4-1BB (CD137) have been found to play major roles as costimulatory receptors for both CD4 and CD8 T cells. In particular, in many situations, they can control proliferation, survival, and cytokine production, and hence are thought to dictate accumulation of protective T cells during anti-viral and anti-tumor responses and pathogenic T cells during autoimmune reactions. As opposed to simply controlling the activity of naïve, effector, and memory T cells, recent data have suggested that both molecules are also instrumental in controlling the generation and activity of so-called regulatory or suppressor T cells (Treg), perhaps in both positive and negative manners. Part of the action on Treg might function to further promote protective or pathogenic T cells, but alternate activities of OX40 and 4-1BB on Treg are also being described that suggest that there might be control by these molecules at multiple levels that will alter the biological outcome when these receptors are ligated. This review specifically focuses on recent studies of regulatory T cells, and regulatory or suppressive activity, that are modulated by OX40 or 4-1BB.

Figure 1

Subsets of Treg Control Effector CD4 and CD8 cells. Regulatory T cells can exist as either natural Treg (nTreg) that derive in the thymus and express CD4 and Foxp3, or as inducible or adaptive Treg (iTreg) that derive in the periphery from naïve CD4+ or CD8+ T cells in response to factors such as TGF-β or IL-10. The latter can be Foxp3+ or Foxp3- and may make suppressive cytokines such as TGF-β or IL-10. Emerging evidence suggests that either nTreg or iTreg limit inflammation and autoimmunity by directly or indirectly suppressing the activity of effector CD4 or CD8 T cells (Th1/Th2/Th17/CTL). Both effector T cells and Treg express surface receptors, either constitutively or inducibly, that can modulate their activity, such as CD28 and CD25, and TNFR superfamily molecules such as OX40, 4-1BB, and GITR.

Figure 2

OX40 and 4-1BB May Exert Multiple Activities in Controlling Treg Generation or Function. OX40 and 4-1BB potentially can modulate Treg activity at several stages. OX40 inhibits development of Foxp3+ iTreg and Foxp3- IL-10-producing Tr1 Treg that are generated from naïve CD4 T cells. Whether 4-1BB possesses this activity is not known. Both OX40 and 4-1BB can promote proliferation and/or survival of already existing Foxp3+ iTreg and nTreg, and also can inhibit the regulatory/suppressive activity of these cells. Whether promotion of proliferation/survival are directly linked to loss of suppressive capacity is not known. OX40 can also downregulate IL-10 secretion, likely linked to loss of suppressive activity by Tr1 Treg. 4-1BB on the other hand can promote the development or expansion of CD8+ Treg that are Foxp3- and may in some cases express CD11c. It is not known if OX40 has the latter capacity.