title: Development of promyelocytic leukemia zinc finger-expressing innate CD4 T cells requires stronger T-cell receptor signals than conventional CD4 T cells.
abstract: MHC class II-expressing thymocytes and thymic epithelial cells can mediate CD4 T-cell selection resulting in functionally distinct thymocyte-selected CD4 (T-CD4) and epithelial-selected CD4 (E-CD4) T cells, respectively. However, little is known about how T-cell receptor (TCR) signaling influences the development of these two CD4 T-cell subsets. To study TCR signaling for T-CD4 T-cell development, we used a GFP reporter system of Nur77 in which GFP intensity directly correlates with TCR signaling strength. T-CD4 T cells expressed higher levels of GFP than E-CD4 T cells, suggesting that T-CD4 T cells received stronger TCR signaling than E-CD4 T cells during selection. Elimination of Ras GTPase-activating protein enhanced E-CD4 but decreased T-CD4 T-cell selection efficiency, suggesting a shift to negative selection. Conversely, the absence of IL-2-inducible T-cell kinase that causes poor E-CD4 T-cell selection due to insufficient TCR signaling improved T-CD4 T-cell generation, consistent with rescue from negative selection. Strong TCR signaling during T-CD4 T-cell development correlates with the expression of the transcription factor promyelocytic leukemia zinc finger protein. However, although modulation of the signaling strength affected the efficiency of T-CD4 T-cell development during positive and negative selection, the signaling strength is not as important for the effector function of T-CD4 T cells. These findings indicate that innate T-CD4 T cells, together with invariant natural killer T cells and γδ T cells, receive strong TCR signals during their development and that signaling requirements for the development and the effector functions are distinct.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiao
authors.forename: Lingqiao
authors.initials: L
authors.lastname: Zhu
authors.forename: Hanief
authors.initials: H
authors.lastname: Sofi
authors.forename: Philip E
authors.initials: PE
authors.lastname: Lapinski
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Kristen
authors.initials: K
authors.lastname: Mueller
authors.forename: Gretta L
authors.initials: GL
authors.lastname: Stritesky
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Hung-Sia
authors.initials: HS
authors.lastname: Teh
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Kappes
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.forename: Derek B
authors.initials: DB
authors.lastname: Sant'Angelo
authors.forename: Cheong-Hee
authors.initials: CH
authors.lastname: Chang
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D004848:Epithelium / Q000276:immunology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C112278:Rasgrp1 protein, mouse; D011948:Receptors, Antigen, T-Cell; C513267:Zbtb16 protein, mouse; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase