p27(kip1) functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes

Although recent in vitro studies have begun to decipher the molecular event s that characterize the anergic state, their in vivo biologic relevance and potential clinical importance remain unclear. Here, using anergic human T- cell clones and tolerant alloreactive mouse T cells that do not induce graf t-versus-host disease, we show that p27(kip1) cyclin-dependent kinase inhib itor is an essential regulator responsible for the blockade of clonal expan sion of anergic T cells in vitro and in vivo. Moreover, in anergic cells, p 27(kip1) associates with the c-Jun co-activator JAB1, resulting in defectiv e transactivation of AP-1 and interleukin 2 transcription. Therefore, pharm acological agents that upregulate the expression of or prevent the degradat ion of p27(kip1) during antigen recognition should be part of new therapeut ic strategies to induce antigen-specific T-cell unresponsiveness.