ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity

Abstract

The role of specialized follicular helper T (TFH) 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-Faslpr (MRLlpr) mouse model of lupus. MRLlpr 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-1lo T cells from MRLlpr mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1lo 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 TFH cells can occur outside the follicle.

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

“…Furthermore, dysregulation of Tfh cells or extrafollicular helper T cells has been linked with development of autoimmunity in several murine models of human lupus and rheumatoid arthritis [19,32,33]. In the present study, CD4 1 ICOS 1 PD-1 1 T cells expanded in RASV-administered MyD88 À/À mice were found to be a mixed population of both Tfh cells (CXCR5 1 ) and extrafollicular helper T cells (CXCR5 À ) (Fig.…”

“…The results of our current study suggest that extra-follicular helper T cells assist in the production of autoantibodies in an IL-21-dependent manner similar to Tfh cells, but that they do not express CXCR5 and that they are located outside the B-cell follicles [19]. Furthermore, dysregulation of Tfh cells or extrafollicular helper T cells has been linked with development of autoimmunity in several murine models of human lupus and rheumatoid arthritis [19,32,33].…”

“…ICOS has been considered an inducible T-cell costimulatory molecule important for CD40-mediated Ab class switching [30]; however, the recent studies of uncontrolled expression of ICOS in several gene-modified mice showing lupus-like pathology provide insight for the close relationship between ICOS-expressing CD4 1 T cells and autoimmunity [19,31]. In the present study, blockade of ICOS using neutralizing Ab significantly reduced the production of total IgG in RASV-administered MyD88 À/À mice, suggesting possible cross-talk between Tfh-like cells and B cells via ICOS-ICOSL interaction for hyper-IgG.…”

“…3A). Since the induction of several cell surface molecules on CD4 1 T cells have been suggested to be closely related to hyper-IgG [19], we determined the expression of PD-1, CD62L, GITR, and CD25 on splenic CD4 1 T cells after RASV challenge. We found expression of PD-1 was drastically increased in the splenic CD4 1 T cells of MyD88 À/À mice compared with those of WT mice after oral RASV challenge (Fig.…”

The Lupus Susceptibility Locus Sle1 Facilitates the Peripheral Development and Selection of Anti-DNA B Cells through Impaired Receptor Editing

“…Furthermore, these cluster-forming IgG2a + 56R + B cells were located in close proximity to CD4 + T cells (Fig. 3C), suggesting that these CD4 + T cells may function as extrafollicular Th cells that induce class-switch recombination (28). Further experiments are needed to define the function and pathological role of these IgG2a 56R + clusters.…”