Immunologically mediated diseases such as asthma, allergies, and autoimmunity are important causes of morbidity. Naturally occurring regulatory T cells (NatTregs) show significant promise as potential tools/targets for immunomodulatory therapies. NatTregs require interleukin (IL) 2 and T cell receptor (TCR) activation to gain maximal suppressive ability. Regulatory T cells can be induced (IndTregs) de novo from T helper (Th)cells by activation in the presence of TGFp. However, little is known about the influence of pro- inflammatory cytokines on Treg function and phenotype. Recent studies including our own suggest an important regulatory role for the proximally induced pro-inflammatory cytokine, IL-6, and the cytokines critical for the adaptive immune response, IL-4and IFN-y, in the development and function of NatTregs and/or IndTregs. The central hypothesis that will be developed in this proposal is that the generation and function of Tregs are influenced by specific cytokines. This has important ramifications in use of Tregs in therapy. To test this hypothesis, we will:
Aim 1 : Investigate the effect of IL-6on FoxPS expression and suppressive function in NatTregs.
Aim 2 : Characterize modulation of IndTregs by cytokines during and after induction. A model of Aspergillus hypersensitivity will be used to investigate IndTreg function in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30ES014776-03
Application #
7485057
Study Section
Special Emphasis Panel (ZRG1-F07-L (20))
Program Officer
Humble, Michael C
Project Start
2006-09-01
Project End
2009-05-31
Budget Start
2008-09-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$39,815
Indirect Cost
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Pillemer, Brendan B L; Qi, Zengbiao; Melgert, Barbro et al. (2009) STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells. J Immunol 183:155-63
Pillemer, Brendan B L; Xu, Hui; Oriss, Timothy B et al. (2007) Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur J Immunol 37:2082-9