title: ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity.
abstract: The role of specialized follicular helper T (T(FH)) cells in the germinal center has become well recognized, but it is less clear how effector T cells govern the extrafollicular response, the dominant pathway of high-affinity, isotype-switched autoantibody production in the MRL/MpJ-Fas(lpr) (MRL(lpr)) mouse model of lupus. MRL(lpr) mice lacking the Icos gene have impaired extrafollicular differentiation of immunoglobulin (Ig) G(+) plasma cells accompanied by defects in CXC chemokine receptor (CXCR) 4 expression, interleukin (IL) 21 secretion, and B cell helper function in CD4 T cells. These phenotypes reflect the selective loss of a population of T cells marked by down-regulation of P-selectin glycoprotein ligand 1 (PSGL-1; also known as CD162). PSGL-1(lo) T cells from MRL(lpr) mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1(lo) T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extrafollicular population of cells that regulates plasma cell differentiation in chronic autoimmunity, indicating that specialized humoral effector T cells akin to T(FH) cells can occur outside the follicle.
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Odegard
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Marks
authors.forename: Leah D
authors.initials: LD
authors.lastname: DiPlacido
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Poholek
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation / Q000502:physiology; D018925:Chemokines / Q000276:immunology; D004195:Disease Models, Animal; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000166:cytology / Q000502:physiology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C514936:CXCR4 protein, mouse; D018925:Chemokines; C556694:Icos protein, mouse; D007074:Immunoglobulin G; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D019718:Receptors, CXCR4; D000098546:Interleukin-21