E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT Abstract A cardinal feature of T lymphocytes is their ability to provide antigen specific immune responses to foreign pathogens while ignoring self-tissues. This self-tolerant state is enforced during T cell development through selection of T cell antigen receptors (TCR) that do not trigger immune responses against self-antigens. The E- protein transcription factors E2A and HEB have been shown to control TCR selection during T cell development. Expression of a self-tolerant TCR leads to activation of the E-protein inhibitor Id3 and consequently suppression of E-protein activities. This regulatory event is both necessary and sufficient for developing T cells passing through selection and reaching maturity. Recent investigations revealed that Id3 deficiency results in acquisition of effector like phenotypes among T cells after TCR selection but prior to stimulation by foreign antigens. This new observation suggests that Id3, in addition to its role in regulating the TCR selection checkpoint, is also needed to prevent premature differentiation from naive T cells into effector and/or memory T cells. One consequence of Id3 disruption in the mouse is development of an autoimmune disorder resembling human Sjogren's syndrome. As in human patients, Id3-/- mice exhibit impaired saliva and tear secretion, lymphocyte infiltration into gland tissues, and pathological damage to salivary and lachrymal glands. How Id3 deletion leads to autoimmune pathology in the gland tissues is not clear. Our recent studies indicate that Id3 controls autoimmunity through regulating the Th2 cytokine IL13. This finding is particularly important since IL13 involvement has been implicated in human patients. Our studies also showed that deletion of Id3 promoted expansion of T helper cells that express IL13. Thus far, little is known about the role of IL13 effector T cells in the development of autoimmunity. Thus, Id3 deficient mouse represents a unique model linking development of IL13 effector T cells with the initiation of an autoimmune disorder. At issue are 1) the underlying mechanism leading to acquisition of the IL13 effector fate and 2) whether premature acquisition of this effector fate among developing T cells plays a direct or indirect role in development of autoimmunity. We propose to further investigate these issues by examining the development and function of IL13 effector T cells in both wild type and Id3 deficient mice. Mechanisms revealed from this study should impact our understanding of Id and E-protein functions in development of IL13 and other parallel effector fates. More importantly, knowledge gained about Id3-mediated regulation of IL13 effectors will provide new strategies for early detection and therapeutic intervention of autoimmune diseases in humans.

Public Health Relevance

The proposed study investigates the role of cytokines and T helper cells in development of autoimmune disorders. The Id3 knockout mouse model used in this study will help provide new strategies for early diagnosis and therapeutic intervention of human Sjogren's syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059638-14
Application #
8633462
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Marino, Pamela
Project Start
1999-08-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$426,667
Indirect Cost
$152,286
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Carico, Zachary M; Roy Choudhury, Kingshuk; Zhang, Baojun et al. (2017) Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire. Cell Rep 19:2157-2173
Zhang, Baojun; Jia, Qingzhu; Bock, Cheryl et al. (2016) Glimpse of natural selection of long-lived T-cell clones in healthy life. Proc Natl Acad Sci U S A 113:9858-63
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Belle, Ian; Mahlios, Josh; McKenzie, Andrew et al. (2014) Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice. Cytokine 69:226-33
Belle, Ian; Zhuang, Yuan (2014) E proteins in lymphocyte development and lymphoid diseases. Curr Top Dev Biol 110:153-87
Zhang, Baojun; Lin, Yen-Yu; Dai, Meifang et al. (2014) Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like ?? T cells. J Immunol 192:1055-1063
Li, Jia; Wu, Di; Jiang, Ning et al. (2013) Combined deletion of Id2 and Id3 genes reveals multiple roles for E proteins in invariant NKT cell development and expansion. J Immunol 191:5052-64
Zhang, Baojun; Dai, Meifang; Li, Qi-Jing et al. (2013) Tracking proliferative history in lymphocyte development with cre-mediated sister chromatid recombination. PLoS Genet 9:e1003887

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