Naive and Innate Memory Phenotype CD4+ T Cells Have Different Requirements for Active Itk for Their Development

Abstract

The Tec family kinase Itk regulates the development of conventional and innate CD8+ T cells. However, little is known about the role of Itk in the development of CD4+ T cell lineages, although the role of Itk in the T cell activation and function is well defined. We show in this study that Itk null mice have increased percentage of CD62LlowCD44high memory phenotype CD4+ T cells compared with wild-type mice. These cells arise directly in the thymus, express high levels of transcripts for the T-bet and IFN-γ and are able to produce IFN-γ directly ex vivo in response to stimulation. Itk deficiency greatly decreases the number of CD4+ T cells with CD62LhighCD44low naive phenotype, but has no effect on the number of memory phenotype CD4+ T cells, indicating that the development of memory phenotype CD4+ T cells is Itk-independent. We further show that the development of the naive phenotype CD4+ T cells is dependent on active Itk signals and can be rescued by expression of Itk specifically in T cells. Our data also show that Itk is required for functional TCR signaling in these cells, but not for the innate function in response to IL-12/IL-18 or Listeria monocytogenes stimulation. These results indicate that CD62LhighCD44low “naive” CD4+ and CD62LlowCD44high “innate memory phenotype” CD4+ T cells may be independent populations that differ in their requirement for Itk signals for development. Our data also suggest that CD4+CD62LlowCD44high memory phenotype T cells have innate immune function.