CMIP requirement in T Follicular helper cell highlights its role in the immunopathogenesis of Idiopathic Nephrotic Syndrome

Abstract

Abstract Follicular helper T (Tfh) cells are a specialized type of CD4 T-cell subset that support B cells during the germinal center (GC) reaction and determine the quality of the humoral response. Tfh development is a multistep process in which multiple extracellular and intracellular signals mediate CD4 T-cell differentiation, migration to lymphoid follicles and positioning in GC. Here we show that deletion of Cmip, an adaptor protein, in CD4 T cells prevents GC development and alters the humoral immune response after immunization. Deletion of Cmip shapes the differentiation of CD4 T cells toward a Th1 phenotype, while the Th2 and Tfh programs are inhibited. Cmip-deficient CD4 T cells display strong STAT5 activation and produce higher IL-2 both under resting conditions and after immunization, suggesting that Cmip deletion induces constitutive activation of the STAT5/IL-2 axis, while the Tfh program is inhibited at the early steps of differentiation. On the other hand, the frequency of Foxp3+CD4 T-cell subset is increased in Cmip-deficient mice. Collectively, these results suggest that Cmip is required for Tfh generation and inhibits Th1 and Treg differentiation. We found that CMIP is upregulated in circulating Tfh of patients with active idiopathic nephrotic syndrome and repressed in remission, pointing out the role of Tfh in the immunopathogenesis of the disease.