Maintenance of immune homeostasis is crucial for survival. In addition to providing effective clearance of pathogens, a carefully balanced immune system must also limit autoimmunity by preventing responses against self-antigens. The recent characterization of T-regulatory (Treg) cells has revealed a major regulatory pathway that is utilized to prevent inappropriate activation of the immune system and maintain homeostasis. T-regulatory cells arise either during thymic development (tTregs), or are generated in the periphery from effector cells exposed to particular cytokine milieu (induced T-regs or iTregs). It is now well established that al Tregs are characterized by the expression of the transcription factor Foxp3, which orchestrates the production of genes that help mediate the effector functions of these cells. Recent work in our laboratory has revealed that the protein kinase PDK1 and the transcription factor NF-?B play a critical role in Treg development and function. In extensive preliminary studies we have now demonstrated a clear involvement of NF-?B as a critical regulator of Treg function. However, exactly how NF-?B influences Treg function remains unclear. In this grant application we will investigate the role of NF-?B in Tregs beyond its role i regulating the expression of Foxp3. In the first aim we will determine whether NF-?B plays a role in Treg differentiation subsequent to FoxP3 expression by deleting NF-?B inducibly. In the second aim, we will characterize the genetic program in Tregs that is controlled by NF-?B. Finally, in the third aim, we will determine which signaling pathway is responsible for activating NF-?B in Tregs, and explore the role of PKC? in this process.

Public Health Relevance

T-regulatory cells (Treg) have emerged as key modulators of the immune system and help prevent the development of autoimmune and inflammatory diseases. Studies from our laboratory have revealed that NF-?B plays a critical role in Treg development and function;however, the mechanism by which NF-?B functions in these cells remains to be fully explained. In this application we are proposing to understand how NF-?B contributes to the function of Tregs! ! !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI068977-07A1
Application #
8487127
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2006-02-01
Project End
2017-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
7
Fiscal Year
2013
Total Cost
$376,000
Indirect Cost
$141,000
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Kang, Jung-Ah; Jeong, Sang Phil; Park, Daeho et al. (2013) Transition from heterotypic to homotypic PDK1 homodimerization is essential for TCR-mediated NF-ýýB activation. J Immunol 190:4508-15
Park, Sung-Gyoo; Long, Meixiao; Kang, Jung-Ah et al. (2013) The kinase PDK1 is essential for B-cell receptor mediated survival signaling. PLoS One 8:e55378
Oh, Hyunju; Ghosh, Sankar (2013) NF-ýýB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev 252:41-51
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Ghosh, Sankar; Hayden, Matthew S (2012) Celebrating 25 years of NF-*B research. Immunol Rev 246:5-13
Baker, Rebecca G; Hayden, Matthew S; Ghosh, Sankar (2011) NF-*B, inflammation, and metabolic disease. Cell Metab 13:11-22
Park, Sung-Gyoo; Mathur, Ramkumar; Long, Meixiao et al. (2010) T regulatory cells maintain intestinal homeostasis by suppressing ?? T cells. Immunity 33:791-803
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Park, Sung-Gyoo; Schulze-Luehrman, Jan; Hayden, Matthew S et al. (2009) The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells. Nat Immunol 10:158-66

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