The role of CDK inhibitors in the regulation of CD4+ T cell effector responses

The antigen-specific responses initiated by TCR recognition of MHC contact are insufficient to initiate a productive immune response. T cells require additional signals provided by the antigen presenting cells, namely costimulatory signal provided by B7-1 (CD80) and B7-2 (CD86), which ligate CD28. CD28 costimulation synergizes with TCR to initiate production of the autocrine growth factor IL-2, which drives proliferation and differentiation of T lymphocytes. The availability of these additional signals can shift the balance between immunity and tolerance by regulating the degree of proliferation and the production of effector cytokines in response to activation. At its most basic level proliferation is critical for an effective immune response since it generates a large population of effector cells from a limited number of naive precursors. A second feature of proliferation is its association with differentiation. Many studies have demonstrated that the probability of a cell being able to produce effector cytokines such as IL-4 or IFNg increases with division. Despite this understanding of the critical role of cell division in the outcome of an immune response, the ways in which the cell cycle is regulated in T lymphocytes is poorly understood. The goals of the studies here were to examine how TCR, CD28 and IL-2 signals are integrated with the cell cycle to promote proliferation, and to determine how cell cycle regulatory molecules influence the decision between anergy/tolerance and effector differentiation. To this end we alleviated specific cell-cycle constraints by eliminating gene products normally involved in negative regulation of cell cycle, namely, p27kip1, and p18ink4c . We have found that the role of these cyclin-dependent kinase inhibitors in T lymphocytes is complex and that each regulates the dynamics of T lymphocyte clonal expansion in a unique fashion. Additionally we have observed that p27 kip1 promotes tolerance induction, and perhaps more surprising that p18ink4c actually opposes tolerance induction. Our data indicate that directly targeting the cell cycle in a specific fashion can redirect the immune response, a finding that has significant implications for induction of tolerance in cases of allograft transplant, or autoimmunity, and for enhancing immune responses to foreign pathogens