TNFRSF4 (OX40, CD134), TNFRSF18 (GITR) and TNFRSF25 are costimulatory receptors that influence CD4+ and CD8+ T cell responses to cognate-antigen. Independently, these receptors have been described to stimulate overlapping functions including enhanced proliferation and activation for both regulatory (CD4+FoxP3+, Treg) and conventional (CD4+FoxP3- or CD8+FoxP3-) T cells. To determine the relative functionality of TNFRSF4, TNFRSF18 and TNFRSF25 in T cell immunity, the activity of TNFRSF4, TNFRSF18 and TNFRS25 agonistic antibodies was compared in the context of both traditional protein/adjuvant (ovalbumin/alum) and CD8+ specific heat shock protein based (gp96-Ig) vaccine approaches. These studies demonstrate that both TNFRSF4, TNFRSF18 and TNFRSF25 independently and additively costimulate vaccine induced CD8+ T cell proliferation following both primary and secondary antigen challenge. In contrast, the activity of TNFRSF4 and TNFRSF25 were observed to be divergent in the costimulation of CD4+ T cell immunity. TNFRSF4 and TNFRSF18 agonists were potent costimulators of ova/alum induced CD4+ conventional T cell proliferation but only weakly costimulated Treg proliferation and IgG2a production, while TNFRSF25 agonists were strong costimulators of Treg proliferation, production of IgG1, IgG2a and IgG2b and weak costimulators of CD4+ Tconv proliferation. Interestingly, antigen-specific cellular and humoral responses were uncoupled upon secondary immunization, which was dramatically effected by the presence of TNFRSF4, TNFRSF18 or TNFRSF25 costimulation. These studies highlight the overlapping but non-redundant activities of these three TNF receptors in T cell immunity, which may guide the application of receptor agonistic agents as vaccine adjuvants for infectious disease and tumor immunity.

Citation Format: Taylor H. Schreiber, Louis Gonzalez, Dietlinde Wolf, Maria Bodero, Eckhard R. Podack. T cell costimulation by TNFRSF4, TNFRSF18, and TNFRSF25 in the context of vaccination. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A38.