biostudies-otherOdegard JMHoward Hughes Medical InstituteNIAMS NIH HHS2873-86https://www.ebi.ac.uk/biostudies/studies/S-EPMC2585848The 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.biostudies-otherEurope PMCUnknown205(12)The Journal of experimental medicinePMC2585848R01 AR040072R01 AR044076AR44076R37 AR040072AR40072Kono DHMarks BRFlavell RACraft JDiPlacido LDDong COdegard JMPoholek ACfalseICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity.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.2008-01-01T00:00:00Z2008 Nov2019-03-27T00:19:27Z2019-03-27T00:19:27ZS-EPMC25858481898123610.1084/jem.20080840