Transient loss of KLF2 expression is essential for CD8 effector T cell expansion.

How T cell expansion, migration, and differentiation are coordinately controlled remains incompletely understood. The KLF2 transcription factor is critical for expression of cell surface molecules, which control lymphocyte traffic, and has been postulated to function as a mediator of T cell quiescence. KLF2 expression is rapidly and transiently silenced in activated T (and other) cells via proteolytic degradation and transcriptional silencing, but why recently activated T cells need to turn off KLF2 expression has remained unknown. Here, functions of transient KLF2 loss have been investigated using a novel mouse model in which expression of a KLF2 point mutant which cannot be proteolytically degraded or transcriptionally silenced is turned on by cre-mediated recombination, such that KLF2 expression and function is continuously maintained in T cells. In response to infection with LCMV, generation of CD4 effector T cells was only slightly decreased. In contrast, generation of CD8 effector T cells was sharply reduced, an effect which was intrinsic to CD8 T cells. Despite this, CD8 T cell proliferation in vitro was only modestly inhibited by constitutive KLF2 expression. These findings document an essential requirement for KLF2 downregulation in expansion of CD8 T cells in vivo, identify unanticipated differences between CD4 and CD8 T cells in their requirements for KLF2 downregulation, and suggest that mechanisms distinct from repression of proliferation underlie the failure of activated CD8 T cells to expand in response to viral infection.