| T cells are vital parts of adaptive immunity,including CD4+ T cells and CD8+ T cells,participate in humoral immunity and cellular immunity.T cells mature in the thymus,migrate to the periphery,and eventually settle in secondary lymphoid organs.Naive T cells,developing from the common progenitor cells in thymus,can be activated by antigens and differentiate to several subsets after antigen clearance.Key transcription factors are the core molecules,regulating the formation and differentiation of cell subsets.There are two contents in this study,comprising: LXRβ regulates the T cell development through the IL-7Rαexpressing during the SP stage;Tcf1 promotes the CD8+Cxcr3+CD62L+ effector T cells formation via regulating the CD62 L expressing.Tcf1 is important in the T cell immunity,especially in CD8+ T cell,however LXRβ is still needed to uncover the function in T cell development.Peripheral naive T cells come from the thymus,and Tcf1 is a key transcription factor affects the development of T cells in the thymus.In addition to Tcf1,we found that LXRβ regulates the survival of single positive thymocytes,then influences peripheral naive T cells.Liver X receptors(LXRs)are key transcription factors in lipid metabolism.There are two isoforms,including α and β(α is encoded by Nr1h3 and β is encoded by Nr1h2).LXRs,ligand-activated nuclear receptors,combine with Retinoic X receptors(RXRs),transfer into nucleus to perform transcription factor activity and regulate the metabolism of cholesterol,fatty acids and phospholipids.The function of LXRs in T cell development is still elusive.We found that the number and frequency of peripheral naive T cells in LXRβ-knockout mice were decreased,thus we explored how the LXRβ impact the peripheral naive T cell formation and the molecular mechanism.We found that only the deficiency of LXRβ affected the peripheral naive T cells,and this was due to the reduction of RTE cells of thymus output,suggesting that the LXRβ impacted peripheral naive T cells through T cell development in thymus.Furthur results revealed that LXRβ affected the single positive thymocytes survival.LXRβ deficiency downregulated the expression of IL-7Rα and Bcl2 in single positive thymocytes,suggesting that LXRβ may regulate the IL-7-Bcl2 axis to influence the cell survival.IL-7 signaling is important during the T cell development,differentiation and survival.The analysis of Ch IP-seq of Il7 r in mouse macrophage showed there was LXRβ binding peak in Il7 r gene loci.Then we confirmed that there was also a LXRβ binding peak in the 3.9kb upsteam of Il7 r in single positive thymocytes,and in vivo Il7r-reporter assay showed the LXRβ could promote the Il7 r transcription at the site of-3.9kb too.In summary,LXRβ is a vital regulator for the single positive thymocytes survival through regulating the IL-7Rα expression.Tcf1(T cell factor 1,encoded by Tcf7),a key transcription factor in the classical Wnt(Wingless)/β-catenin signaling pathway,contains a high mobility group(HMG)DNA-binding domain in its C-termini and a β-catenin binding domain in the N-termini,which can cooperate with β-catenin to initiate the downstream.Tcf1 has the histone deacetylase(HDAC)activity,the first transcription factor that directly modifies histone acetylation,to bridge transcriptional and epigenetic regulation.Tcf1 is a crucial regulator in CD8+ T cell immunity.During acute infection,Tcf1 positively regulates the EOMES-IL-2Rβaxis to facilitate the Tcm formation.Tcf1 can prevent CD8+ T exhaustion in chronic infection and tumor too.There is a subset maintaining Tcf1 expression during early activation,which has the strong potential differentiating into Tcm.However,Tcf1 is a nuclear factor,which can not be the suitable biomarker for Tcm precursors.The lack of Tcm precursors surface biomarkers limit its further study,especially in application.Herein,we conjoint analysed the single cell RNA-seq datas of CD8+ effector T cells and memory T cells,and uncovered the Cxcr3+CD62L+ effectors as the Tcm-like cells,which had the strong latent capacity differentiating into Tcm directly.Cxcr3+CD62L+ effectors had the similar cytokine-secreting ability and transcrption factors expression pattern with Tcm.Tcf1 was the key regulator for the Cxcr3+CD62L+ effectors formation,and vital during the Cxcr3+CD62L+ effectors differentiating into Tcm.The molecular mechanism was Tcf1 can bind to the +10.3kb site of Sell(CD62L encoding gene)gene locus,then promote the CD62 L expression,which can faciliate the generation of Cxcr3+CD62L+ effectors.We established a in vitro culture system,which can induce the na(?)ve CD8+ T cells to be Cxcr3+CD62L+effectors efficiently.We aimed to explored a new method to build the Tcm pool covering the TCR repertoire to exert the Tcm advantage.Give all that,we uncovered the role of LXRβ in regulating T cell development for the first time,and found that LXRβ affects single positive thymocytes survival through regulating Il-7R α expression to influence peripheral naive T cell status.In addition to LXRβ,Tcf1 is the key regulator for the generation of Cxcr3+CD62L+ effector T cells,and Cxcr3+CD62L+effector T cells has the powerful potential as the cellular vaccine. |