ICOS-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 ¹⁰ 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 ¹⁰ T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extra- follicular population of cells that regulates plasma cell differentiation in chronic autoim- munity, indicating that specialized humoral effector T cells akin to T _FH cells can occur outside the follicle.