title: 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.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Prince
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kraus
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Carty
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Caleb
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Yin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; Leslie.Berg@umassmed.edu.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Berg
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D005434:Flow Cytometry; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; C491198:Eomes protein, mouse; D019409:Interleukin-15; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020825:T-Box Domain Proteins; C513267:Zbtb16 protein, mouse; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase