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The Homeostasis But Not the Differentiation of T Cells Is Regulated by p27^Kip11

Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202; and Walther Cancer Institute, Indianapolis, IN 46208

The cyclin-dependent kinase inhibitor p27^Kip1 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 p27^Kip1 to differentiate into Th subsets. We observed increased Th2 differentiation in p27^Kip1-deficient cultures. In addition to increases in CD4⁺ and CD8⁺ T cells, there is a similar increase in T cells in p27^Kip1-deficient mice compared with wild-type mice. The increase in Th2 differentiation is correlated to an increase of IL-4 secretion by CD4⁺DX5⁺TCR⁺CD62L^low 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 p27^Kip1 and STAT4 or STAT6. In contrast, the increased proliferation and differentiative capacity of p27^Kip1-deficient T cells has no effect on the ability of STAT4/p27^Kip1- or STAT6/p27^Kip1-deficient CD4⁺ cells to differentiate into Th1 or Th2 cells, respectively. Thus, while p27^Kip1 regulates the expansion and homeostasis of several T cell subsets, it does not affect the differentiation of Th subsets.

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