Regulatory T cells are crucial for the control of immune-mediated pathology during organ transplant rejection and autoimmune disease, therefore understanding the underlying mechanisms by which these cells function will be critical for promoting immune tolerance in humans. Recent studies in experimental models have established that Foxp3, which is a member of the forkhead family of DNA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function. and therefore is crucial for acquired immune tolerance. Expression of Foxp3 initiates a unique transcriptional program which includes the induction of genes such as GITR, CD25, CTLA-4, IL-10 and TGF2, and repression of pro-inflammatory cytokine genes such as IL-2 and IFN?. The mechanisms by which Foxp3 enforces this genetic program are unclear. The studies proposed in this application are centered around basic questions of how Foxp3 binds to target genes, and how Foxp3 represses or induces transcription at these loci. The proposed studies will add significantly to our understanding of how Foxp3 regulates gene expression, and the information gained from these studies will have relevance for the design of novel therapeutic strategies by which tolerance can be promoted in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070807-03
Application #
7749570
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2008-01-15
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$366,424
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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