TNF type 2 receptor (p75) lowers the threshold of T cell activation

T cell activation requires a threshold amount of TCR-mediated signals, an a mount that is reduced by signals mediated through costimulatory molecules e xpressed on the T cell surface. Here the role of TNFR2 (p75) as a putative costimulatory receptor for T cell activation was examined. It was found tha t p75 deficiency in CD8(+) T cells increased the requirements for TCR agoni st approximately 5-fold. Furthermore, p75(-/-) T cells display a marked red uction in the proliferative response to TCR agonist. This hypoproliferative response was associated with delayed kinetics of induction of the acute ac tivation markers CD25 and CD69 as well as a marked decrease in the producti on of IL-2 and IFN-gamma. The net result is that very few cells are recruit ed into the dividing population. Interestingly, CD28 costimulation was only partially effective in rescuing the proliferative defect of p75(-/-)CD8(+) T cells. Thus, p75 provides an important costimulatory signal in addition to that provided by CD28 toward optimal T cell proliferation.