Study On The Function Of Transcription Factor T-bet In Regulating Follicular Helper T Cell Response During Acute Viral Infection

Because of the complexity and diversity of pathogen,the organism has developed a highly organized and well-adapted immune system to eliminate invaders.In order to defensing different microorganisms,the immune system elicits optimal responses according to the specie of microbes.For example,intracellular microbes would induce Type 1 immune response,which consists of IFN?-producing group1 innate lymphoid cells?ILC1 and natural killer cells?,CD4⁺Type 1 T helper cells?Th1?,and CD8⁺Type 1 cytotoxic T cells?TC1?;venoms or helminthes would induce Type 2 immune response,which includes IL4-producing ILC2s,Th2 cells,and TC2 cells;extracellular bacteria or fungi would induce Type 3 immune response,which comprises IL17-producing ILC3s,Th17 cells,and TC17 cells.Such phenomenon reflects the plasticity and the environmental dependency of immune cells.Follicular helper T cell?TFH?is a CD4⁺helper T cell subset specialized for helping germinal center reaction.TFH cells express high level of CXCR5 to locating at lymphoid follicles.In the light zone of GC,they provide crucial signals to antigen-specific B cells and promote somatic hyper-mutation,class switch recombination?CSR?,and affinity maturation of GC B cells by ligand-receptor binding and cytokine secretion.Besides,TFH cells also facilitate the differentiation of B cells into memory B cells and long-lived plasma cells.TFH cells have been reported to play important roles in Type 1 immune response?e.g.malaria?,Type 2 immune response?e.g.intestinal helminth infection?,or Type 3 immune response?e.g.primary biliary cholangitis?.TFH cells derived from diverse microenvironment share similar differentiation process with each other:at the initiate phase of TFH cell differentiation,the expression of some transcription factors?such as Bcl6,Ascl2 and TCF1?is up regulated in some certain activated CD4⁺T cell,which promotes CXCR5 expression;Next,CXCR5⁺Bcl6⁺TFH precursor cells localize to the T-B border zone where they receive more differentiation signals from activated B cells.After this engagement,they reinforce Bcl6expression and surface markers such as PD1,ICOS,migrating towards GCs,where they provide helper signals to B cells.Except for these similarities,TFH cell is also endowed with some particular characteristics by distinct microbes.Previous study shows that TFH cells also express lineage-specific transcription factors?TFs?as their conventional counterpart when defensing different types of pathogens,such as T-bet,GATA-3,or ROR?t in Type 1,2,or 3immune response.These TFs promote the production of IFN?,IL4,or IL17 in TFH cells respectively,which would help B cells to switch to optimal antibody class in order to clear corresponding microbes.However,the extent to which TFH cells rely on these TFs is not clear.Transcription factor T-bet was originally discovered as the lineage marker of Th1 cells.Later it was found to be extensively expressed by multiple different lymphocyte lineages during Type I immune response,which including both innate and adaptive immune cell subsets.For innate immune cells,T-bet in NK could promote its early differentiation and terminal maturation;T-bet in ILC and??T cell could promote its IFN?production;T-bet in DC could enhance its Th1-priming capacity;T-bet in NKT cell could up-regulate its CD122level and promote survival.For adaptive immune cells,T-bet in CD4⁺T cell could up-regulate Th1 differentiation and inhibit polarization of other CD4⁺T cell subsets such as Th2 or Th17;in CD8⁺T cell,T-bet could promote its terminal differentiation and enhance its Granzyme B secretion;T-bet in B cell could promote the survival of memory B cells and enhance IgG2 switching.Therefore,these facts together highlight T-bet as the master regulator of Type 1 immune response.In Type 1 immune response,activated antigen-specific CD4⁺T helper cell mainly differentiates into Th1 and TFH cell subsets.Most studies focus on the function of T-bet in Th1 differentiation and function,while generally considering it as a suppressor for TFH differentiation.However,the exact role of T-bet in TFH cell response is much less understood.In this study,using a combined conditional/inducible knockout system,we mainly investigated the role of T-bet in regulating TFH cell development in LCMV infection model and other infection/immunization model.Besides,we also compared the transcriptome of T-bet dependence in TFH and Th1 cell by analyzing Microarray results derived from T-bet^+/+or T-bet^-/-Th1/TFH cells.The in vivo results showed that transcription factor T-bet slightly inhibit TFH cell early differentiation but promote later mainteinance of TFH cells during type1 immune response.Our findings demonstrate the crucial and specific role of T-bet in“Type1”TFH cell response,which suggests that modulation of T-bet expression in TFH cell may be a powerful therapeutic target for treating infection diseases,transplant rejection,cancer and autoimmune disease.