Abstract
Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-kappaB pathway in regulating mature T cell function by using CD4+ T cells from p50-/- cRel-/- mice, which exhibit virtually no inducible kappaB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-kappaB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-kappaB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-kappaB-inducing IkappaB kinase beta showed that NF-kappaB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-kappaB in both IL-2 and Akt-induced survival pathways. In vivo, p50-/- cRel-/- mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-kappaB proteins in regulating T cell function in vivo and establish a critically important function of NF-kappaB in TCR-induced regulation of survival.