title: NKAP Regulates Invariant NKT Cell Proliferation and Differentiation into ROR-γt-Expressing NKT17 Cells.
abstract: Invariant NKT (iNKT) cells are a unique lineage with characteristics of both adaptive and innate lymphocytes, and they recognize glycolipids presented by an MHC class I-like CD1d molecule. During thymic development, iNKT cells also differentiate into NKT1, NKT2, and NKT17 functional subsets that preferentially produce cytokines IFN-γ, IL-4, and IL-17, respectively, upon activation. Newly selected iNKT cells undergo a burst of proliferation, which is defective in mice with a specific deletion of NKAP in the iNKT cell lineage, leading to severe reductions in thymic and peripheral iNKT cell numbers. The decreased cell number is not due to defective homeostasis or increased apoptosis, and it is not rescued by Bcl-xL overexpression. NKAP is also required for differentiation into NKT17 cells, but NKT1 and NKT2 cell development and function are unaffected. This failure in NKT17 development is rescued by transgenic expression of promyelocytic leukemia zinc finger; however, the promyelocytic leukemia zinc finger transgene does not restore iNKT cell numbers or the block in positive selection into the iNKT cell lineage in CD4-cre NKAP conditional knockout mice. Therefore, NKAP regulates multiple steps in iNKT cell development and differentiation.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Puspa
authors.initials: P
authors.lastname: Thapa
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Meibo W
authors.initials: MW
authors.lastname: Chen
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: McWilliams
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Belmonte
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Constans
authors.affiliation: Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901.
authors.forename: Derek B
authors.identifier: 0000-0002-5510-9367
authors.initials: DB
authors.lastname: Sant'Angelo
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and Shapiro.virginia1@mayo.edu.
authors.forename: Virginia Smith
authors.initials: VS
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C494812:Bcl2l1 protein, mouse; D016207:Cytokines; D020381:Interleukin-17; C560431:NKAP protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012097:Repressor Proteins; D051020:bcl-X Protein; D015847:Interleukin-4