Development of Innate CD4+ and CD8+ T Cells in Itk-Deficient Mice Is Regulated by Distinct Pathways

Abstract

T cell development in the thymus produces multiple lineages of cells, including innate T cells such as γδ TCR+ cells, invariant NKT cells, mucosal-associated invariant T cells, and H2–M3-specific cells. Although innate cells are generally a minor subset of thymocytes, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8+ T cells develop as innate cells with characteristics of memory T cells. Thus, in Itk-deficient mice, mature CD4−CD8+ (CD8 single-positive [SP]) thymocytes express high levels of the transcription factor eomesodermin (Eomes) and are dependent on IL-4 being produced in the thymic environment by a poorly characterized subset of CD4+ thymocytes expressing the transcriptional regulator promyelocytic leukemia zinc finger. In this study, we show that a sizeable proportion of mature CD4+CD8− (CD4SP) thymocytes in itk−/− mice also develop as innate Eomes-expressing T cells. These cells are dependent on MHC class II and IL-4 signaling for their development, indicating that they are conventional CD4+ T cells that have been converted to an innate phenotype. Surprisingly, neither CD4SP nor CD8SP innate Eomes+ thymocytes in itk−/− or SLP-76(Y145F) mice are dependent on γδ T cells for their development. Instead, we find that the predominant population of Eomes+ innate itk−/− CD4SP thymocytes is largely absent in mice lacking CD1d-specific invariant NKT cells, with no effect on innate itk−/− CD8SP thymocytes. In contrast, both subsets of innate Eomes+itk−/− T cells require the presence of a novel promyelocytic leukemia zinc finger–expressing, SLAM family receptor adapter protein–dependent thymocyte population that is essential for the conversion of conventional CD4+ and CD8+ T cells into innate T cells with a memory phenotype.