Regulation of conventional versus innate CD8+ T cell development in the thymus is now known to produce a wide array of distinct T cell lineages. Many of these T cell subsets play key roles in regulating immune responses, both to self as well as to pathogens. In addition to the conventional CD4+ and CD8+ ???T cells that are key components of the adaptive immune response, there are regulatory T cells, NKT cells, ?? T cells, and a variety of additional innate T cell subsets. The appropriate balance of T cells developing into each of these lineages is essential to maintain immunological homeostasis, self-tolerance, and the ability to produce both rapid and delayed responses to pathogenic infections. Currently, the molecular mechanisms governing these developmental lineage choices are under intense investigation. Our own studies have identified a signaling pathway involving the Tec family tyrosine kinase, Itk, which determines conventional versus innate CD8+ T cell development. In wild-type (WT) thymocytes with normal Itk function, MHC class I-specific T cells predominantly develop into conventional naive CD8+ T cells, which are precursors of effector cytotoxic T cells. In addition, a very minor subset of cells develop into innate CD8+ T cells that have characteristics of previously-activated memory CD8+ T cells, and exhibit immediate effector function when activated. In contrast to this, MHC class I-specific thymocytes lacking the Tec kinase, Itk, develop nearly exclusively into innate CD8+ T cells that express high levels of the T-box transcription factor, Eomesodermin. These findings indicate that a signaling pathway requiring Itk regulates the lineage decision between conventional and innate CD8+ T cells. As Itk is well known as a component of the TCR signaling pathway leading to phospholipase?-31 activation and actin polymerization, these data also implicate altered TCR signaling as a modulator of these key T cell lineage decisions. To determine the transcriptional regulators of this lineage decision, we performed a microarray experiment to identify factors differentially expressed between WT conventional and Itk-deficient innate CD8+ thymocytes. Interestingly, this analysis indicated that the single most highly up-regulated transcription factor in WT relative to Itk-deficient CD8+ thymocytes is IRF4;further, our preliminary studies indicate that in the absence of IRF4, nearly all CD8+ T cells also develop into the innate lineage. In contrast, the transcription factor most highly expressed in Itk- deficient thymocytes relative to WT is Runx2. We hypothesize that Itk signaling promotes conventional CD8+ T cell development by inducing the transcription of IRF4, and that in the absence of Itk, Runx2 upregulation converts conventional CD8+ T cells into innate T cells, leading to upregulation of Eomesodermin. To determine the importance of these transcription factors in regulating conventional versus innate CD8+ T cell development we propose to examine whether IRF4 is essential for conventional CD8+ T cell lineage commitment. We will also investigate whether IRF4 is sufficient to suppress Eomesodermin expression in CD8+ T cells. Third, we will determine whether different strengths of TCR signaling lead to graded expression of IRF4. Finally, we will examine whether Runx2 is required for innate CD8+ T cell development.

Public Health Relevance

Our immune system protects us against a wide array of pathogens using many different types of white blood cells. The work described in this proposal will investigate how our body produces the correct types of white blood cells in the correct proportions. This understanding will aid in efforts to regulate and control the immune system to fight infections and eradicate cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI084987-01A1
Application #
8041181
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Prabhudas, Mercy R
Project Start
2010-09-30
Project End
2011-08-31
Budget Start
2010-09-30
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$411,250
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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
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
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
Nayar, Ribhu; Schutten, Elizabeth; Bautista, Bianca et al. (2014) Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J Immunol 192:5881-93
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
Yin, Catherine C; Cho, Ok Hyun; Sylvia, Katelyn E et al. (2013) The Tec kinase ITK regulates thymic expansion, emigration, and maturation of ?? NKT cells. J Immunol 190:2659-69
Joseph, Raji E; Kleino, Iivari; Wales, Thomas E et al. (2013) Activation loop dynamics determine the different catalytic efficiencies of B cell- and T cell-specific tec kinases. Sci Signal 6:ra76
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
Berg, Leslie J (2012) Signaling pathways that regulate T cell development and differentiation. J Immunol 189:5487-8

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