Plasticity of T helper cell differentiation

描述（由申请人提供）：为了保护免受各种不同病原体的侵害，T细胞在响应每种感染时获得不同的效应子功能。对于CD 4 + T细胞，这些效应子功能的特征在于由效应子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CD 4+效应T细胞亚群，并且可以在受控刺激条件下从幼稚CD 4+前体产生。功能不同的CD 8+效应T细胞的类似亚群也已被描述。虽然这一领域的早期工作表明效应T细胞分化与个体发育过程中发生的终末分化过程相当，但最近的证据表明T细胞效应亚群在其分化状态中更具可塑性。一些T细胞不仅表现出 虽然CD 4+和CD 8+效应T细胞同时具有多于一种效应谱系的特征，但也观察到在应答过程中获得新的细胞因子谱的CD 4+和CD 8+效应T细胞的其他情况。例如，在某些条件下，CD 4 + Th 17细胞将获得产生IFN γ的能力，而Th 1细胞将成为分泌IL-21的Tfh细胞。这些数据表明，T细胞反应可以随着时间的推移而演变，导致在免疫反应的不同阶段占主导地位的效应器功能的改变。重要的是，这一过程可能在自身免疫反应的演变中发挥关键作用，也可能有助于慢性炎症性疾病的发病机制。我们假设转录抑制因子Blimp-1是T细胞可塑性的关键调节因子。Blimp-1在活化的CD 4+和CD 8 + T细胞中被特定的细胞因子亚群（包括IL-2、IL-12和IL- 4）上调;因此，Blimp-1在CD 4+效应Th 1和Th 2细胞中表达，但在Th 17细胞中不表达，以及在I型效应CD 8 + T细胞中表达。我们发现，从Blimp-1缺陷的幼稚CD 4 + T细胞产生的Th 1细胞获得了多谱系分子程序，表达Th 1和Th 17特异性基因;在LCMV感染后，在Blimp-1缺陷的CD 8 + T细胞中观察到类似的基因表达变化。这些数据表明，Blimp- 1通常起抑制Th 17和Tc 17分化的作用，并且进一步地，可能是效应细胞维持高度极化的Typ I亚群身份所需的。为了验证这一假设，我们将首先研究Blimp的分子调控 1转录，以确定在免疫应答的不同阶段Blimp-1表达的模式。然后，我们将确定Blimp-1和/或Bcl-6的分级表达是否在Th 17依赖性自身免疫性疾病的发展过程中和病毒感染过程中调节I型效应细胞与17型效应细胞的分化。最后，我们将确定是否需要持续的Blimp-1表达来维持I型谱系的身份，以及是否在效应T细胞中有条件地缺失Blimp-1会改变其效应功能，并促进其诱导自身免疫的能力。总之，这些研究将确定Blimp-1表达的幅度和持续时间是否对维持T细胞分化状态至关重要，以及免疫应答期间Blimp-1表达的改变是否有助于效应器功能的可塑性。这些数据将提供重要的见解， 致病性T细胞反应导致自身免疫和其他疾病的机制。

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.