title: CD4(+) type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes.
abstract: Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, S-405 30 Gothenburg, Sweden.
authors.forename: Nadir
authors.initials: N
authors.lastname: Kadri
authors.forename: Eva
authors.initials: E
authors.lastname: Korpos
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Claire
authors.initials: C
authors.lastname: Briet
authors.forename: Linda
authors.initials: L
authors.lastname: Löfbom
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Agnes
authors.initials: A
authors.lastname: Lehuen
authors.forename: Christian
authors.initials: C
authors.lastname: Boitard
authors.forename: Dan
authors.initials: D
authors.lastname: Holmberg
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cardell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D060890:B7-H1 Antigen / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D004195:Disease Models, Animal; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein / Q000502:physiology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000145:classification / Q000276:immunology* / Q000637:transplantation; D010179:Pancreas / Q000276:immunology; D010195:Pancreatitis / Q000517:prevention & control; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D055610:Antigens, CD1d; D060890:B7-H1 Antigen; C526879:Cd1d1 protein, mouse; C498919:Cd274 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D011948:Receptors, Antigen, T-Cell