The Study Of TRIM37 And ECM1 In Follicular Helper T Cell Differentiation And Function

High-affinity antibodies derived from the germinal centre(GC)are critical to protective immunity against pathogen invasion.The generation of high-affinity antibody is dependent on follicular helper T(TFH)cell.TFH cells promote GC formation,antibody affinity maturation,isotype class switching,plasma cell differentiation,and memory B cell development.Many studies have shown that defects in TFH cell development or function led to severe infections in humans.Hence,mutations in TFH cell-related key genes may be the cause of recurrent infection in patients.TFH development is dependent on transcription regulator BCL6.Bcl6 deletion in CD4+T completely abrogates TFH cell development and subsequent high-affinity antibody production.Many TFH cell key transcription factors,including STAT3,TCF1,LEF1,and BATF,positively regulate BCL6 and TFH cell differentiation,while BLIMP 1,FOXO1,and STAT5 negatively regulate BCL6 and TFH cell differentiation.In addition,OPN-I promotes TFH development by protecting BCL6 against ubiquitin-dependent proteasome degradation.However,the detailed mechanisms for the post-transcriptional modification of the BCL6 protein in TFH cells are not clear.In part Ⅰ study,we have identified Trim37 gene variants with a statistically significant association with recurrent infection by performing burden tests.Trim37 mutant mice were susceptible to influenza virus infection.These data were highly consistent with the immunological features of Mulibrey Nanism(caused by Trim37 mutation).Trim37 mutant mice showed the defect of TFH cell differentiation,GC formation,and high-affinity antibody production.Mechanistically,TRIM3 7 directly interacts with BCL6 through its MATH domain,and catalyzed the K27/29-linked polyubiquitination of BCL6,thereby,preventing BCL6 from proteasome-mediated degradation.Our data reveal that TRIM37-BCL6 axis is critical for TFH cell differentiation and antibody production.We demonstrate that respiratory tract infections in Mulibrey nanism patients may be ascribed to the defect of TFH cell differentiation.Identification of new strategies may provide an inroad into improving protective immunity against recurrent infection or treatments for Mulibrey Nanism disease.Many reports have demonstrated that IL-6 and IL-21 promotes TFH differentiation by up-regulating BCL6.In contrast,IL-2 inhibits TFH differentiation by up-regulating the level of STAT5 phosphorylation and down-regulating BCL6.A previous study has demonstrated that extracellular matrix protein 1(ECM1)is highly expressed in TH2 cells and down-regulates the level of STAT5 phosphorylation.Based on the notion that the higher concentration of IL-2 in the microenvironment,we hypothesize that ECM1 promotes TFH cell differentiation by antagonizing the IL-2-STAT5 signaling pathway.We uncovered that ECM1 was induced by IL-6 and IL-21 in TFH cells.ECM1 upregulates BCL6 expression by antagonizing the IL-2-STAT5 signaling pathway,thereby,promotes TFH differentiation.At the same time,Ecm1-/-mice exhibit the defects of TFH cell differentiation,GC formation,and antigen-specific antibody production.While exogenous recombinant ECM1 protein significantly promotes TFH cell differentiation,GC response,and high affinity neutralizing antibody production during influenza virus infection.Our data illustrate that ECM1,a soluble factor involved in the microenvironment cytokine niche,promotes TFH cell differentiation.Our work provides a new strategy for vaccine design and develops therapeutic methods against virus infection.