We have recently defined the surface phenotype of a subset of CD8+ T cells programmed to inhibit the activation and expansion of follicular helper T cells (TFH). These regulatory CD8+ T cells express CD44, CD122 and the inhibitory Ly49 receptor on their surface and a T cell receptor (TCR) that recognizes Qa- 1: peptide complexes expressed by TFH cells. These CD8+ Treg cells, which represent less than 5% of the CD8+ T cell pool, inhibit TFH activity through an IL-15- and perforin-dependent mechanism. The development of collagen-induced arthritis (CIA) is associated with B- and T-lymphocyte responses, production of anti-collagen type II antibodies and collagen-specific T cells. Our preliminary studies of a mouse model of CIA support the hypothesis that enhanced interactions between CD8+ Treg cells and target TFH cells profoundly inhibits disease progression. In this proposal, we further define the interaction between CD8+ Treg and target TFH cells in CIA and a murine model of systemic autoimmunity - B6.-Yaa disease - in an effort to develop strategies that increase the activity of CD8+ Treg and inhibit and/or ameliorate disease development. The experimental approaches outlined below should provide new insights into the role of CD8+ Treg in the regulation of autoimmune diseases and form the basis for new therapeutic approaches to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and related diseases.

Public Health Relevance

Rheumatoid arthritis (RA) and spondyloarthritis affect ~3 million Americans. Approximately 1 million Americans are afflicted with SLE and related systemic autoimmune diseases. We have made substantial progress in understanding these autoimmune disorders during the last grant period. We propose to utilize these insights to develop new therapeutic approaches to these disorders using mouse models of RA and SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037562-16
Application #
8390465
Study Section
Special Emphasis Panel (ZRG1-IMM-N (03))
Program Officer
Esch, Thomas R
Project Start
1996-07-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
16
Fiscal Year
2013
Total Cost
$444,227
Indirect Cost
$178,292
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