OX40 (CD134) is a 50 kD type I transmembrane glycoprotein in the TNFR superfamily, containing 3 full cysteine rich domains, and a relatively short cytoplasmic tail, and although a monomer it signals as a trimer when bound to OX40L, its known ligand in the TNF family. OX40 is not constitutively expressed on naïve CD4 or CD8 T cells but is induced after antigen recognition. High-level expression can result under inflammatory and tolerogenic conditions in vivo, and OX40 can be maintained for a number of days under adjuvant-induced inflammatory conditions. However, OX40 is constitutively present on the surface of Foxp3+ nTreg, and constitutive or inducible on Foxp3+ iTreg. Similarly, OX40L is inducible and has been found on activated/mature APC such as dendritic cells, B cells, and macrophages. OX40 is downregulated after the effector phase of T cell responses, but might be retained at low levels on subpopulations of memory T cells as well as Treg. It is rapidly re-expressed at high levels on effector/memory T cells once antigen is seen again. Our early studies of OX40 in vivo used knockout animals made deficient in OX40 or blocking studies with antibody preventing OX40L binding to OX40. These demonstrated that both primary CD4 and CD8 T cell responses and development of memory to protein antigen in adjuvants (e.g. CFA, alum), or to several viruses, or to a range of tumors are strongly controlled by OX40. The poor responses were largely due to weak expansion of naïve T cells, which translated to fewer T cells surviving to become memory. Our studies in OX40-deficient animals have additionally been supported by experiments using stimulatory antibodies which promote an increase in the number of primary effector and memory T cells that develop, again suggesting that a major role of OX40 signals is to regulate effector T cell division and expansion and survival, and suppress apoptosis. We have identified several molecular targets such as Bcl-xL, Bcl-2, and survivin, along with upstream signaling intermediates such as PI-3-kinase, Akt, and the canonical and non-canonical NF-κB pathways that control the activities of OX40. Several studies have also suggested that OX40 signals can directly prevent suppressive activity of nTreg and can inhibit the induction of iTreg which further aid the clonal expansion and differentiation of effector T cells. Studies in experimental animal models have now not only stressed the importance of OX40 and OX40L for autoimmune and inflammatory disease manifestations, but shown that inhibiting this interaction can be useful therapeutically. For example, inhibiting OX40/OX40L interactions can abrogate Th2 or Th1/Th17-induced pathologies in experimental leishmaniasis, EAE, graft-versus-host disease, transplantation, inflammatory bowel disease, asthma, and collagen-induced arthritis. These studies have highlighted the broad reaching control of T cell responses by OX40 and OX40L, and promoted this interaction to the forefront of potential therapies aimed at dampening T cell driven immune diseases. Agonist reagents that stimulate OX40 also have great potential therapeutically for vaccination, as shown by a number of studies in tumor models or of responses to viruses where the immune response can be boosted dramatically to aid protection. The lab is currently focusing on how OX40 drives responses to allergens that link to asthmatic and allergic disease, and how OX40 synergizes with other TNFR family or non-TNFR family molecules to control allergen-reactive T cells. Understanding this is likely to lead to combination therapeutic approaches for allergic disease.
Bansal-Pakala, P., Jember, A. G-H, and Croft, M. 2001. Signaling through OX40 (CD134) breaks peripheral T cell tolerance. Nature Medicine. 7:907.
Rogers, P.R., Song, J., Gramaglia, I., Killeen, N., and Croft, M. 2001. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity. 15:445.
Salek-Ardakani, S., Song, J., Halteman, B.S., Jember, A. G-H., Akiba, H., Yagita, H., and Croft, M. 2003. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. Journal of Experimental Medicine. 198:315
Song, J., Cheng, M., Tang, X., and Croft, M. 2005. Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion. Immunity 22:621.
So, T., and Croft, M. 2007. Cutting Edge: OX40 inhibits TGF-β and antigen-driven conversion of naïve CD4 T cells into CD25+Foxp3+ T cells. Journal of Immunology. 179:1427.
So, T., Soroosh, P., Eun, S-Y., Altman, A., and Croft, M. 2011. An antigen-independent signalosome of CARMA1, PKCθ, and TRAF2 determines NF-κB signaling in T cells. Proceedings of the National Academy of Sciences. 108:2903.
Salek-Ardakani, S., Flynn, R., Arens, R., Yagita, H., Smith, G.L., Borst, J., Schoenberger, S.P., and Croft, M. 2011. The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice. Journal of Clinical Investigation. 121:296.
Boettler, T., Moeckel, F., Cheng, Y., Heeg, M., Salek-Ardakani, S., Crotty, S., Croft, M., and Von Herrath, M. 2012. OX40 facilitates control of a persistent virus infection. PLoS Pathogens. 8:e1002913.
Lei, F., Song, J., Haque, R., Haque, M., Xiong, X., Fang, D., Croft, M., and Song, J. 2013. Regulation of A1 by OX40 contributes to CD8+ T cell survival and anti-tumor activity. PLoS One. 8:e70635.
Mehta, A.K., Duan, W., Doerner, A.M., Traves, S.L., Broide, D.H., Proud, D., Zuraw, B.L., and Croft, M. 2015. Rhinovirus infection interferes with the induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. Journal of Allergy and Clinical Immunology 10.1016/j.jaci.2015.05.007