Autoantibody-inducing CD4 T (aiCD4 T) cell that induces systemic lupus erythematosus (SLE) includes not only follicular helper T cell but also IL-21-producing CXCR5−ICOShiPD-1hi cell

Abstract

Abstract Objective We found that repeated immunization with antigen induces systemic lupus erythematosus (SLE) in mice, and we have then proposed a novel ‘self-organized criticality theory’ that autoimmunity takes place when host’s immune system is overstimulated by repeated exposure to antigen to levels that surpass the immune system’s stability limit. A novel T cell type which we termed autoantibody-inducing CD4 T (aiCD4 T) cell was newly generated via TCR revision at periphery. They not only stimulated B cells to generate varieties of autoantibodies but also helped differentiation of CD8 T cell into CTL to induce tissue injuries. We also showed that the aiCD4 T cell belongs to CD45RBlo122lo CD4 T cell subpopulation. Here we further dissected the phenotype of aiCD4 T cell. Methods BALB/c mice were repeatedly immunized with OVA and SLE was induced. Cell surface marker of CD45RBlo CD4 T cell was detected using flow cytomery. These CD4 T cells were stimulated with anti-CD3 and CD28 antibodies in vitro, and cytokine in culture supernatant was detected using ELISA. Results After repeated immunization with OVA, CD4+CXCR5+ICOShiPD-1hi follicular helper T (Tfh) cell was increased, and these Tfh cells were CD45RBlo. Further, CXCR5−ICOShiPD-1hi cell was also increased in CD45RBlo CD4 T cell of OVA-immunized mice. We found that CXCR5−ICOShiPD-1hi CD4 T cell highly produced IL-21 rather than Tfh cell after repeated immunization with OVA. Conclusion In addition to Tfh cell, the CXCR5−ICOShiPD-1hi CD4 T cell that produces IL-21 was increased in line with induction of SLE. This novel CXCR5−ICOShiPD-1hi CD4 T cell population appears to be responsible for helping B cell to induce varieties of autoantibodies and driving CD8 T cell to cause lupus tissue injury.