RNA editing enzyme ADAR1 is required for early T cell development

The RNA editing enzyme ADAR1 has been shown to be an essential molecule for hematopoietic cell differentiation,embryonic development,and regulation of immune responses.Here,we present evidence in a T-cell-specific gene knockout mouse model that ADAR1 is required for early T cell development.Loss of ADAR1 led to cell death of the progenitors at the double negative stage and prevented T cell maturation in the thymus.Furthermore,ADAR1 deletion in pre-T cells preferentially affected TCRb-expressing cells causing TCRb positive cell depletion.Interruption of IFN signaling occurred in the premature T cells,indicating a role of IFN signaling in the survival of TCRb-expressing cells regulated by ADAR1.This study demonstrated an essential role for the RNA editing enzyme ADAR1 as a potential regulator for T-cell fate determination during clonal selection,which,in turn,contributes to immunologic homeostasis.

Using mouse models to study function of transcriptional factors in T cell development

Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells(HSCs)which are responsible for replenishing all blood cells.Transcriptional factors play important role in hematopoiesis.In this review we compile several studies on using genetic modified mice and humanized mice to study function of transcriptional factors in lymphopoiesis,including T lymphocyte and Natural killer(NK)cell development.Finally,we focused on the key transcriptional factor Bcl11b and its function in regulating T cell specification and commitment.

Helicobacter pylori neutrophil-activating protein:From molecular pathogenesis to clinical applications

Helicobacter pylori (H. pylori) neutrophil-activating protein (HP-NAP) was originally identified as a virulence factor of H. pylori for its ability to activate neutrophils to generate respiratory burst by releasing reactive oxygen species. Later on, HP-NAP was also found to be involved in the protection of H. pylori from DNA damage, supporting the survival of H. pylori under oxidative stress. This protein is highly conserved and expressed by virtually all clinical isolates of H. pylori. The majority of patients infected with H. pylori produced antibodies specific for HP-NAP, suggesting its important role in immunity. In addition to acting as a pathogenic factor by activating the innate immunity through a wide range of human leukocytes, including neutrophils, monocytes, and mast cells, HP-NAP also mediates adaptive immunity through the induction of T helper cell type I responses. The pro-inflammatory and immunomodulatory properties of HP-NAP not only make it play an important role in disease pathogenesis but also make it a potential candidate for clinical use. Even though there is no convincing evidence to link HP-NAP to a disease outcome, recent findings supporting the pathogenic role of HP-NAP will be reviewed. In addition, the potential clinical applications of HP-NAP in vaccine development, clinical diagnosis, and drug development will be discussed.

Trap1a is an X-linked and cell-intrinsic regulator of thymocyte development

The X-linked Trap1a gene encodes the tumor rejection antigen P1A,which is expressed in fetal tissues and multiple lineages of tumor cells.The function of this gene remains unknown.Using chimeric mice with wild-type(WT)and Trap1a^(−/y)bone marrow,we show that Trap1a^(−/y)donor cells are capable of generating most lineages of hematopoietic cells,with the notable exception of T cells.Deletion of Trap1a selectively arrests T-cell development at double-negative stage 1(DN1,with a CD4^(−)CD8^(−)CD25^(−)CD44^(+)phenotype).Because Trap1a is expressed in Lin^(−)Sca-1^(+)c-Kit^(+)and common lymphoid progenitors but not in immature thymocytes(DN1-DN4),Trap1a mutations affect the differentiation potential of progenitor cells without directly acting on T cells.Despite a similarity in the blockade of DN1 to DN2 transition,the Trap1a^(−/y)DN1 cells have normal expression of c-Kit,in contrast to what was reported in the Notch1^(−/−)DN1.Complementary DNA profiling of Trap1a^(−/y)and WT embryonic stem cells shows that Trap1a does not regulate the Notch pathway.Our data reveal that Trap1a is an X-linked regulator that affects the differentiation potential of progenitor cells into T cells through a Notch-independent mechanism and identify an important function for the Trap1a gene.

Medullary thymic epithelial cells,the indispensable player in central tolerance

Crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and the establishment of central tolerance.Medullary thymic epithelial cells(mTECs) play important roles in the late stage of T cell development,especially negative selection and Treg generation.The function of mTECs is highly dependent on their characteristic features such as ectopic expression of peripheral tissue restricted antigens(TRAs) and their master regulator-autoimmune regulator(Aire),expression of various chemokines and cytokines.In this review,we summarize the current understanding of cellular and molecular mechanisms of mTEC development and its functions in T cell development and the establishment of central tolerance.The open questions in this field are also discussed.Understanding the function and underlying mechanisms of mTECs will contribute to the better control of autoimmune diseases and the improvement of immune reconstitution during aging or after infection,chemotherapy or radiotherapy.

Thymic-specific regulation of TCR signaling by Tespa1

Double-positive(DP)thymocytes undergo positive selection to become mature single-positive CD4+and CD8+T cells in response to T cell receptor(TCR)signaling.Unlike mature T cells,DP cells must respond to low-affinity self-peptide-MHC ligands before full upregulation of their surface TCR expression can occur.Thus,DP thymocytes must be more sensitive to ligands than mature T cells.A number of molecules have been found that are able to enhance the strength of the TCR signal to facilitate positive selection.However,almost all of these molecules are also active in mature T cells.Themis(thymocyte expressed molecule involved in selection)and Tespa1(thymocyte expressed positive selection associated 1)are two recently discovered molecules essential for optimal TCR signaling and thymocyte development.A deficiency in both molecules leads to defects in positive selection.Here,we compared the relative contributions of Themis and Tespa1 to positive selection in thymocytes.We show that Tespa1 deficiency led to more limited and specific gene expression profile changes in cells undergoing positive selection.In mixed bone marrow transfer experiments,Tespa1^(−/−)cells showed more severe defects in thymocyte development than Themis^(−/−)cells.However,Tespa1^(−/−)cells showed a substantial degree of homeostatic expansion and became predominant in the peripheral lymphoid organs,suggesting that Tespa1 is a thymic-specific TCR signaling regulator.This hypothesis is further supported by our observations in Tespa1 conditional knockout mice,as Tespa1 deletion in peripheral T cells did not affect TCR signaling or cell proliferation.The different regulatory effects of Tespa1 and Themis are in accordance with their nonredundant roles in thymocyte selection,during which Tespa1 and Themis double knockouts showed additive defects.

Th17细胞与Treg细胞调控肿瘤免疫的研究进展

辅助性T细胞的新亚群Th17,主要分泌IL-17A、IL-17F、IL-21和IL-22等细胞因子,并特异性表达转录因子ROR-γt,能够在IL-6/IL-21与TGF-β(小鼠)或IL-6/IL-23与IL-1β(人)的作用下由初始CD4+T细胞分化而来。Th17细胞在宿主防御微生物感染、介导炎症反应以及自身免疫病方面具有重要作用。调节性T细胞(Regulatory T cell,Treg)又被称为抑制性T细胞,在TGF-β的作用下由初始T细胞分化而来,主要分泌TGF-β、IL-10等细胞因子,并特异性表达转录因子Foxp3。Treg能够通过抑制效应T细胞活性介导免疫耐受,阻止组织损伤。Th17与Treg细胞在肿瘤发展进程中具有重要作用,并且在肿瘤免疫中的作用都具有双重性。同时,肿瘤微环境中两者具有发育可塑性,能够在肿瘤微环境中处于动态平衡。因此,深入而全面的研究Th17和Treg细胞变得尤为重要。文章综述了Th17以及Treg细胞的特性以及在调控肿瘤免疫中的作用,以便更加全面的了解和掌握它们,为科学研究提供理论基础。