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.
The generation of protective immunity that reduces or prevents re-infection with the same pathogen is a hallmark of the immune system. One key component of this process is the formation of distinct types of effector T cells, each of which provides the appropriate response to a specific subset of infecting pathogens. Our studies will elucidate the biochemical pathways that are required for the generation of these distinct types of effector T cells.
|Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naÃ¯ve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9|
|Sharma, Shruti; Campbell, Allison M; Chan, Jennie et al. (2015) Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc Natl Acad Sci U S A 112:E710-7|
|Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena et al. (2015) A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression. J Immunol 195:4822-31|
|Wu, Tuoqi; Shin, Hyun Mu; Moseman, E Ashley et al. (2015) TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection. Cell Rep 12:2099-110|
|Kapoor, Varun N; Shin, Hyun Mu; Cho, Ok Hyun et al. (2014) Regulation of tissue-dependent differences in CD8+ T cell apoptosis during viral infection. J Virol 88:9490-503|
|Prince, Amanda L; Watkin, Levi B; Yin, Catherine C et al. (2014) Innate PLZF+CD4+ Î±Î² T cells develop and expand in the absence of Itk. J Immunol 193:673-87|
|Prince, Amanda L; Kraus, Zachary; Carty, Shannon A et al. (2014) Development of innate CD4+ and CD8+ T cells in Itk-deficient mice is regulated by distinct pathways. J Immunol 193:688-99|
|Shin, Hyun Mu; Kapoor, Varun N; Guan, Tianxia et al. (2013) Epigenetic modifications induced by Blimp-1 Regulate CD8âº T cell memory progression during acute virus infection. Immunity 39:661-75|
|Malhotra, Nidhi; Narayan, Kavitha; Cho, Ok Hyun et al. (2013) A network of high-mobility group box transcription factors programs innate interleukin-17 production. Immunity 38:681-93|