Plasticity of T helper cell differentiation

T辅助细胞分化的可塑性

• 批准号: 8833242
• 负责人: LESLIE JOAN BERG
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-25 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833242
• 关键词: Address; Alleles; Area; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; Biochemical Pathway; Blimp-1 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell Lineage; Cells; ChIP-seq; Characteristics; Chronic; Cytokine Signaling; Data; Development; Disease; Disease model; Effector Cell; Evolution; Exhibits; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Growth; Health; Helper-Inducer T-Lymphocyte; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammatory; Interferons; Interleukin-12; Interleukin-17; Interleukin-2; Interleukin-4; Lymphocytic choriomeningitis virus; Maintenance; Modeling; Molecular; Molecular Analysis; Nucleic Acid Regulatory Sequences; Pathogenesis; Pattern; Plastics; Play; Process; Production; Regulation; Reporter Genes; Retroviridae; STAT protein; STAT3 gene; STAT4 gene; STAT6 gene; Signal Pathway; Staging; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Th1/Th2 Differentiation Pathway; Th2 Cells; Time; Transcription Repressor/Corepressor; Transgenic Mice; Virus; Virus Diseases; Work; base; chemokine receptor; cytokine; cytotoxic; in vitro Assay; in vivo; infectious disease model; insight; pathogen; prevent; programs; research study; response; trait; transcription factor

DESCRIPTION (provided by applicant): For protection against a wide array of diverse pathogens, T cells acquire distinct effector functions in response to each infection. For CD4+ T cells, these effector functions are characterized by the predominant cytokines produced by the effector cells. To date, five different subsets of CD4+ effector T cells have been described, and can be generated from na¿ve CD4+ precursors under controlled stimulation conditions. Similar subsets of functionally distinct CD8+ effector T cells have also been described. While early work in this area indicated that effector T cell differentiation was comparable to the terminal differentiation processes that occur during ontogeny, recent evidence indicates that T cell effector subsets are more plastic in their differentiation status. Not only do some T cells exhibit characteristics of more than one effector lineage at the same time, but additional instances of CD4+ and CD8+ effector T cells acquiring new cytokine profiles over the course of a response have also been observed. For instance, under certain conditions, CD4+ Th17 cells will acquire the capacity to produce IFNgamma, and Th1 cells will become IL-21-secreting Tfh cells. These data suggest that T cell responses can evolve over time, leading to alterations in the effector functions that predominate at different stages of an immune response. Importantly, this process is likely to play a key role in the evolution of autoimmune responses and may also contribute to the pathogenesis of chronic inflammatory diseases. We hypothesize that the transcriptional repressor, Blimp-1, is a critical regulator of T cell plasticity. Blimp-1 is upregulated in activatd CD4+ and CD8+ T cells by a specific subset of cytokines, including IL-2, IL-12, and IL- 4; thus, Blimp-1 is expressed in CD4+ effector Th1 and Th2, but not Th17, cells, as well as in Type I effector CD8+ T cells. We find that Th1 cells generated from Blimp-1-deficient na¿ve CD4+ T cells acquire a multi- lineage molecular program, expressing both Th1- and Th17-specific genes; a similar change in gene expression is seen in Blimp-1-deficient CD8+ T cells following LCMV infection. These data suggest that Blimp- 1 normally functions to repress Th17 and Tc17 differentiation, and further, may be required for effector cells to maintain a highly polarized Typ I subset identity. To test this hypothesis, we will first examine the molecular regulation of Blimp 1 transcription by distinct cytokines to determine the pattern of Blimp-1 expression at different stages of the immune response. We will then determine whether graded expression of Blimp-1 and/or Bcl-6 regulate Type I versus Type 17 effector cell differentiation during the development of a Th17-dependent autoimmune disease and during virus infection. Finally, we will determine whether persistent Blimp-1 expression is required to maintain Type I lineage identity, and whether conditional deletion of Blimp-1 in effector T cells alters their effector functions, and promotes their ability to induce autoimmunity. Together, these studies will determine whether the magnitude and duration of Blimp-1 expression are critical in the maintenance of T cell differentiation states, and whether alterations in Blimp-1 expression during an immune response contribute to the plasticity of effector functions. These data will provide important insights into the mechanisms contributing to autoimmune and other diseases caused by pathogenic T cell responses.

描述（由申请人提供）：为了保护T细胞免受多种不同病原体的侵害，T细胞在每种感染中获得不同的效应功能。对于CD4+ T细胞，这些效应功能的特点是由效应细胞产生的主要细胞因子。迄今为止，已经描述了五种不同的CD4+效应T细胞亚群，并且可以在受控刺激条件下由单一CD4+前体产生。类似的功能不同的CD8+效应T细胞亚群也已被描述。虽然该领域的早期研究表明，效应T细胞分化与个体发育过程中的终末分化过程相当，但最近的证据表明，T细胞效应亚群的分化状态更具可塑性。不仅仅是一些T细胞