title: Innate PLZF+CD4+ αβ T cells develop and expand in the absence of Itk.
abstract: T cell development in the thymus produces multiple lineages of cells, including innate T cells. Studies in mice harboring alterations in TCR signaling proteins or transcriptional regulators have revealed an expanded population of CD4(+) innate T cells in the thymus that produce IL-4 and express the transcription factor promyelocytic leukemia zinc finger (PLZF). In these mice, IL-4 produced by the CD4(+)PLZF(+) T cell population leads to the conversion of conventional CD8(+) thymocytes into innate CD8(+) T cells resembling memory T cells expressing eomesodermin. The expression of PLZF, the signature invariant NKT cell transcription factor, in these innate CD4(+) T cells suggests that they might be a subset of αβ or γδ TCR(+) NKT cells or mucosal-associated invariant T (MAIT) cells. To address these possibilities, we characterized the CD4(+)PLZF(+) innate T cells in itk(-/-) mice. We show that itk(-/-) innate PLZF(+)CD4(+) T cells are not CD1d-dependent NKT cells, MR1-dependent MAIT cells, or γδ T cells. Furthermore, although the itk(-/-) innate PLZF(+)CD4(+) T cells express αβ TCRs, neither β2-microglobulin-dependent MHC class I nor any MHC class II molecules are required for their development. In contrast to invariant NKT cells and MAIT cells, this population has a highly diverse TCRα-chain repertoire. Analysis of peripheral tissues indicates that itk(-/-) innate PLZF(+)CD4(+) T cells preferentially home to spleen and mesenteric lymph nodes owing to increased expression of gut-homing receptors, and that their expansion is regulated by commensal gut flora. These data support the conclusion that itk(-/-) innate PLZF(+)CD4(+) T cells are a novel subset of innate T cells.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Prince
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Watkin
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Yin
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Liisa K
authors.initials: LK
authors.lastname: Selin
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20814.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and 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; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000276:immunology / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D006183:H-2 Antigens; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; C513267:Zbtb16 protein, mouse; D001613:beta 2-Microglobulin; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase