We have made major progress in all of the original specific aims of our investigations of the factors that regulate a murine autoimmune disease during the last grant support period. Our analysis of the relationship between expression of an autoreactive T cell receptor and virally-induced autoimmune disease indicated an important role for central tolerance (negative selection). However, the relative impact of central and self-tolerance mechanisms in disease prevention could not be directly assessed. We are now in a good position to define the relative contributions of central and peripheral tolerance mechanisms to the generation and maintenance of self-tolerance in the experimental plan that we propose for the next period of requested grant support. First, we will continue to delineate the molecular basis of aTCR-coupled signaling pathway that culminates in thymocyte negative selection (SA1) and use this information to test the effects of defective central tolerance on the development of autoimmune disease (SA2). In SA3, we will establish the impact of peripheral regulation on self-tolerance, using mice deficient in either regulatory CD4+ or CD8+ T cells. These studies will allow a clear separation of the contribution of peripheral T cell regulation from central (deletional) tolerance mechanisms. Our progress over the past grant period has provided us with the experimental and conceptual foundations that will allow us to define the relative impact of central and peripheral mechanisms in maintenance of self-tolerance and prevention of autoimmunity after either viral infection or deliberate exposureto self-antigens in the context of heightened innate immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037562-14
Application #
7743807
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
1996-07-01
Project End
2011-11-30
Budget Start
2010-01-01
Budget End
2011-11-30
Support Year
14
Fiscal Year
2010
Total Cost
$403,144
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Nakagawa, Hidetoshi; Sido, Jessica M; Reyes, Edwin E et al. (2016) Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity. Proc Natl Acad Sci U S A 113:6248-53
Kim, Hye-Jung; Barnitz, R Anthony; Kreslavsky, Taras et al. (2015) Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 350:334-9
Alvarez Arias, Diana A; Kim, Hye-Jung; Zhou, Penghui et al. (2014) Disruption of CD8+ Treg activity results in expansion of T follicular helper cells and enhanced antitumor immunity. Cancer Immunol Res 2:207-16
Leavenworth, Jianmei W; Tang, Xiaolei; Kim, Hye-Jung et al. (2013) Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells. J Clin Invest 123:1382-9
Holderried, Tobias A W; Lang, Philipp A; Kim, Hye-Jung et al. (2013) Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection. Proc Natl Acad Sci U S A 110:21089-94
Kim, Hye-Jung; Wang, Xuan; Radfar, Soroosh et al. (2011) CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A 108:2010-5
Kim, Hye-Jung; Cantor, Harvey (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol 23:446-52
Kim, Hye-Jung; Verbinnen, Bert; Tang, Xiaolei et al. (2010) Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467:328-32
Egli, Dieter; Sandler, Vladislav M; Shinohara, Mari L et al. (2009) Reprogramming after chromosome transfer into mouse blastomeres. Curr Biol 19:1403-9