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

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.