title: Pak2 Controls Acquisition of NKT Cell Fate by Regulating Expression of the Transcription Factors PLZF and Egr2.
abstract: NKT cells constitute a small population of T cells developed in the thymus that produce large amounts of cytokines and chemokines in response to lipid Ags. Signaling through the Vα14-Jα18 TCR instructs commitment to the NKT cell lineage, but the precise signaling mechanisms that instruct their lineage choice are unclear. In this article, we report that the cytoskeletal remodeling protein, p21-activated kinase 2 (Pak2), was essential for NKT cell development. Loss of Pak2 in T cells reduced stage III NKT cells in the thymus and periphery. Among different NKT cell subsets, Pak2 was necessary for the generation and function of NKT1 and NKT2 cells, but not NKT17 cells. Mechanistically, expression of Egr2 and promyelocytic leukemia zinc finger (PLZF), two key transcription factors for acquiring the NKT cell fate, were markedly diminished in the absence of Pak2. Diminished expression of Egr2 and PLZF were not caused by aberrant TCR signaling, as determined using a Nur77-GFP reporter, but were likely due to impaired induction and maintenance of signaling lymphocyte activation molecule 6 expression, a TCR costimulatory receptor required for NKT cell development. These data suggest that Pak2 controls thymic NKT cell development by providing a signal that links Egr2 to induce PLZF, in part by regulating signaling lymphocyte activation molecule 6 expression.
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Kyle L
authors.identifier: http://orcid.org/0000-0003-0460-4410
authors.initials: KL
authors.lastname: O'Hagan
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Olga
authors.initials: O
authors.lastname: Pryshchep
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Chyung-Ru
authors.initials: CR
authors.lastname: Wang
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 hyewonp@amgen.com.
authors.forename: Hyewon
authors.identifier: http://orcid.org/0000-0002-1942-0414
authors.initials: H
authors.lastname: Phee
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000276:immunology; D051767:Early Growth Response Protein 2 / Q000096:biosynthesis*; D049452:Green Fluorescent Proteins / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013950:Thymus Gland / Q000276:immunology; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; C513267:Zbtb16 protein, mouse; D049452:Green Fluorescent Proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases