The adaptive immune system is an extremely efficient means of eliminating specific pathogens while sparing host tissues. However, this efficiency is dependent on balance;unrestrained immunity can lead to autoimmune disease while a sluggish response can lead to chronic infections and cancer. Regulatory T cells (Tregs) play a critical role in maintaining this balance by suppressing the immune response to self and maintaining immune homeostasis. Tregs utilize many distinct mechanisms to mediate suppression of the immune response. Interleukin-35 (IL-35), a cytokine from the IL-12 family, has emerged as an important soluble mediator of suppression. IL-35 is secreted as a heterodimer of two protein chains, the IL-12 subunit p35 and Epstein-Barr Virus induced gene 3 (Ebi3). IL-35 is a potent inhibitor of immune cell proliferation in vitro and in vivo. Tregs express the genes encoding IL-35 constituitively, while effector T cells do not. However, when naive CD4 T cells are stimulated in the presence of IL-35, they begin to secrete it themselves. Interestingly, the genes encoding p35 and Ebi3 are not generally expressed in T cells;rather, they are utilized by antigen-presenting cells to make cytokines that stimulate the immune response. As such, the regulation of these genes in T cells is still unclear. This research proposal suggests experiments that will propel our understanding of how IL-35 can be regulated in T cells, and elucidate the molecular mechanisms used by IL-35 to mediate suppression of T cell proliferation and conversion to IL-35 producing cells. Understanding these mechanisms is of crucial importance when developing new strategies targeting autoimmunity and cancer.

Public Health Relevance

Regulatory T cells play a critical role in providing balance to the immune system. These cells are critical for protection against autoimmune diseases, and also inhibit immunity to cancers. Our research seeks to determine how regulatory T cells modulate immunity;elucidating these pathways is critical to developing better treatments for both autoimmunity and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI098383-01
Application #
8255282
Study Section
Special Emphasis Panel (ZRG1-F07-E (20))
Program Officer
Prograis, Lawrence J
Project Start
2012-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$49,214
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Delgoffe, Greg M; Woo, Seng-Ryong; Turnis, Meghan E et al. (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501:252-6
Delgoffe, Greg M; Vignali, Dario A A (2013) STAT heterodimers in immunity: A mixed message or a unique signal? JAKSTAT 2:e23060