Plasticity of T helper cell differentiation

描述(由申请人提供)：为了保护不同种类的病原体，T细胞对每一种感染都有不同的效应器功能。对于CD4T细胞，这些效应器功能的特征是由效应器细胞产生的主要细胞因子。到目前为止，已经描述了五种不同的CD4效应T细胞亚群，它们可以在受控刺激条件下从原始的CD4前体细胞中产生。功能不同的CD8效应T细胞的相似亚群也已被描述。虽然这一领域的早期研究表明，效应器T细胞的分化与个体发育过程中的末端分化过程类似，但最近的证据表明，T细胞效应器亚群的分化状态更具可塑性。不仅一些T细胞表现出 同时观察到多个效应器谱系的特征，但也观察到CD4和CD8效应器T细胞在应答过程中获得新的细胞因子谱的更多实例。例如，在一定条件下，CD4Th17细胞将获得产生IFNGamma的能力，Th1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变化。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CD4和CD8T细胞中被IL-2、IL-12和IL-4等细胞因子亚群上调；因此，Blimp-1在CD4效应器Th1和Th2细胞中表达，但不在Th17细胞中表达，也在I型效应器CD8T细胞中表达。我们发现，由Blimp-1缺陷的原始CD4T细胞产生的Th1细胞获得多谱系分子程序，表达Th1和Th17特异性基因；LCMV感染后，Blimp-1缺陷的CD8 T细胞的基因表达也发生了类似的变化。这些数据表明，Blimp-1正常发挥抑制Th17和Tc17分化的功能，此外，效应细胞可能需要维持高度极化的I型亚群身份。为了验证这一假设，我们将首先检查Blimp的分子调控 1由不同的细胞因子转录，以确定Blimp-1在免疫反应的不同阶段的表达模式。然后，我们将确定在Th17依赖型自身免疫性疾病的发展过程中和在病毒感染期间，Blimp-1和/或Bcl-6的分级表达是否调节I型和17型效应细胞的分化。最后，我们将确定是否需要持续表达Blimp-1来维持I型谱系身份，以及在效应器T细胞中有条件地删除Blimp-1是否改变其效应器功能，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，以及免疫反应期间Blimp-1表达的变化是否有助于效应器功能的可塑性。这些数据将为 致病T细胞反应引起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.