Role of the stress kinase pathway in signaling via the T cell costimulatory receptor 4-1BB

4-1BB is a member of the TNFR superfamily expressed on activated CD4(+) and CD8(+) T cells, 4-1BB can costimulate IL-2 production by resting primary T cells independently of CD28 ligation. In this study, we report signaling e vents following 4-1BB receptor aggregation using an A(k)-restricted costimu lation-dependent T cell hybridoma, C8.A3. Aggregation of 4-1BB on the surfa ce of C8.A3 cells induces TNFR-associated factor 2 recruitment, which in tu rn recruits and activates apoptosis signal-regulating kinase-l, leading to downstream activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). 4-1BB ligation also enhances anti-CD3-induced JNK/SAPK activati on in primary T cells. Overexpression of a catalytically inactive form of a poptosis signal-regulating kinase-l in C8.A3 T cells interferes with activa tion of the SAPK cascade and with IL-2 secretion, consistent with a critica l role for JNK/SAPK activation in 4-1BB-dependent IL-2 production, Given th e ability of both CD28 and 4-1BB to induce JNK/SAPK activation, me asked wh ether hyperosmotic shock, another inducer of this cascade, could function t o provide a costimulatory signal to T cells, Osmotic shock of resting prima ry T cells in conjunction with anti-CD3 treatment was found to costimulate IL-2 production by the T cells, consistent with a pivotal role for JNK/SAPK in T cell costimulation.