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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Marshall, Nikki B; Vong, Allen M; Devarajan, Priyadharshini et al. (2017) NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection. J Immunol 198:1142-1155
Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naïve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9
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
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
Nayar, Ribhu; Schutten, Elizabeth; Jangalwe, Sonal et al. (2015) IRF4 Regulates the Ratio of T-Bet to Eomesodermin in CD8+ T Cells Responding to Persistent LCMV Infection. PLoS One 10:e0144826
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
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
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+ ?? T cells develop and expand in the absence of Itk. J Immunol 193:673-87
Shin, Hyun Mu; Kapoor, Varun; Guan, Tianxia et al. (2013) Epigenetic modifications induced by Blimp-1 Regulate CD8? T cell memory progression during acute virus infection. Immunity 39:661-75

Showing the most recent 10 out of 11 publications