The Homeostasis But Not the Differentiation of T Cells Is Regulated by p27Kip1

Abstract

The cyclin-dependent kinase inhibitor p27Kip1 is a critical regulator of T cell proliferation. To further examine the relationship of T cell proliferation and differentiation, we examined the ability of T cells deficient in p27Kip1 to differentiate into Th subsets. We observed increased Th2 differentiation in p27Kip1-deficient cultures. In addition to increases in CD4+ and CD8+ T cells, there is a similar increase in γδ T cells in p27Kip1-deficient mice compared with wild-type mice. The increase in Th2 differentiation is correlated to an increase of IL-4 secretion by CD4+DX5+TCRαβ+CD62Llow T cells but not to increased expansion of differentiating Th2 cells. While STAT4- and STAT6-deficient T cells have diminished proliferative responses to IL-12 and IL-4, respectively, proliferative responses are increased in T cells doubly deficient in p27Kip1 and STAT4 or STAT6. In contrast, the increased proliferation and differentiative capacity of p27Kip1-deficient T cells has no effect on the ability of STAT4/p27Kip1- or STAT6/p27Kip1-deficient CD4+ cells to differentiate into Th1 or Th2 cells, respectively. Thus, while p27Kip1 regulates the expansion and homeostasis of several T cell subsets, it does not affect the differentiation of Th subsets.