Regulation Of T Follicular Help Cell Response By Histone Methyltransferase EZH2 During Acute Viral Infection

Initial CD4⁺T cells can be activated through the interaction of T-cell receptor-antigen peptide/MHC class II complex,and then differentiated into effector T cells to participate in the immune response process.Due to the regulation of different antigens and external microenvironment,CD4⁺T cells can be induced to express specific transcription factors and differentiated into subgroups with different functions and characteristics.During acute viral infection,CD4⁺T cells were mainly differentiated into T_H1 cells and follicular help cells(T_FH cells).T_FH cells are considered to be an important subset of CD4⁺T cells because of their ability to assist pathogen-specific B cells to produce and maintain Germinal center?GC?responses and promote the maturation and differentiation of GC B cells into plasma cells,which can produce high-affinity antibodies to effectively fight infection.The differentiation of T_FH cells is a multistage and multifactorial process.Currently,it is known that Bcl6,Tfc1,STAT family members,C-MAF,IRF-4,Ascl2,Blimp1 and other regulatory factors are involved in the differentiation and regulation of T _FHH cells.Due to its important auxiliary role in the humoral immune response,the dysfunction of T_FH cells can mediate a variety of pathophysiological processes,including immune deficiency,autoimmune diseases and tumors.In view of the carical role of T _FH cells in humoral immunity,the regulation of developmental mechanisms of T_FH cells has become a hot topic in immunology.In this study,we investigated the effect of EZH2?an important methylated transferase in the epigenetic modification?on the differentiation of T_FH cells under acute viral infection model.EZH2 is a major component of the polycomb repressive complex 2?PRC2?and provides histone methylation transferase activity that catalyzes trimethylation of H3K27?H3K27me3?.Ezh2-mediated H3K27me3 is an inhibitory histone modification that is associated with chromatin densification and gene silencing,and has been reported to be involved in the differentiation of T_H1,T_H2,Treg and T_FR cells.However,the regulation of EZH2 on the differentiation process of T_FH cells has not been reported yet.So we used conditioned knockout mice in the model of acute viral infection to observe the role of EZH2 in the differentiation process of T_FH cells through different experimental designs,and to reveal the effect of EZH2 on the effector function of T_FH cells.Microarry technology and overexpression experiments were also used to explore the possible mechanism of EZH2regulating T_FH cell differentiation.The results suggest that EZH2 plays an important role in T_FH cell differentiation and immune response,and such differentiation regulation mainly occurs in the early stage of infection.Accordingly,the absence of EZH2 can seriously damage the differentiation of T_FH cells in a cell-autonomous manner.Moreover,such influence directly leads to the decrease of T_FH cells'auxiliary function to B cells,and impair the humoral immune response.In addition,in vitro inhibition experiments can be observed that T _FH cell differentiation defects caused by the absence of EZH2 can be achieved through specific inhibition of H3K27me3,and such inhibition can be significantly limited by Bcl6overexpression.Through this study,we revealed the important role of EZH2 in the differentiation of T_FH cells during acute viral infection,which enables us to have a deeper understanding of the regulation of T_FH cells differentiation,and also explains the differentiation choice of T_FH cells at epigenetic regulation level.It will provide potential therapeutic targets for the design of T_FHH cells-related vaccines and adjuvants as well as targeted strategies for the treatment of T_FH cells differentiation abnormalities or T_FHH cells-related immune diseases.