Development of innate CD4+ and CD8+ T cells in Itk-deficient mice is regulated by distinct pathways

• Published in: The Journal of immunology (1950) Vol. 193; no. 2; pp. 688 - 699
• Main Authors: Prince, Amanda L, Kraus, Zachary, Carty, Shannon A, Ng, Caleb, Yin, Catherine C, Jordan, Martha S, Schwartzberg, Pamela L, Berg, Leslie J
• Format: Journal Article
• Language: English
• Published: United States 15-07-2014
• Subjects: Animals; Antigens, CD1d - immunology; Antigens, CD1d - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Proliferation; Flow Cytometry; Interleukin-15 - deficiency; Interleukin-15 - genetics; Interleukin-15 - immunology; Interleukin-4 - immunology; Interleukin-4 - metabolism; Kruppel-Like Transcription Factors - immunology; Kruppel-Like Transcription Factors - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Promyelocytic Leukemia Zinc Finger Protein; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - immunology; Rats; Receptors, Antigen, T-Cell, alpha-beta - immunology; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; T-Box Domain Proteins - immunology; T-Box Domain Proteins - metabolism; Thymocytes - immunology; Thymocytes - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302059

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.