Project Details
Description
PROJECT SUMMARY/ABSTRACT
CD4+FOXP3+lymphocytes are expanded within the intestinal inflammatory lesion of Crohn’s disease (CD);
however, ongoing inflammation belies presumed anti-inflammatory function of this cell. FOXP3 is required for
differentiation and function of T regulatory (TREG) cells. FOXP3-mediated gene repression is lost in intestinal
T cells of CD patients. Indeed, “FOXP3+ Crohn’s cell (FOXP3+CD)” bears a transcriptional signal more
closely related to the pro-inflammatory TH17 cell. Derivation, function, and therapeutic implications of the
FOXP3+CD cell remain poorly understood. Our long-term goal is to dissect epigenetic mechanisms regulating
TREG cellular differentiation and function in the setting of GI inflammation. Consequently, the objective is to
identify mechanisms responsible for activation of the TH17 phenotypic transcriptional network within intestinal
FOXP3+CD cells and test therapeutic opportunities to restore their regulatory function in vivo. Our central
hypothesis is that a shared chromatin configuration between TREG and TH17 cells allows for rapid activation
of a TH17-like pro-inflammatory gene program in intestinal FOXP3+TREG cells. A set of TH17-relevant genes
are accessible, yet not active in human TREG cells. A defining feature of the TH17 program was significant
enrichment of CCCTC binding factor (CTCF) motifs. CTCF, a well-known topologically-associated domain
(TAD) insulator protein, also mediates intra-TAD chromosomal looping and enhancer-promoter interaction
regulating gene transcription. Bioinformatic analysis of this TH17 program indicates an inhibitory role for
Polycomb Repressor Complex 1 (PRC1). Deletion of PRC1 in murine FOXP3+ cells led to secretion of
prototypic TH17-like cytokines in FOXP3+ cells, and spontaneous colitis. The rationale is that with mechanistic
insight into the biology of intestinal TREG cell in inflammation, one can apply targeted FOXP3+ CD cell-directed
therapy including engineering of human TREG cells for adoptive cell therapy trials. To test the central
hypothesis and obtain the overall objective we will address the following three questions: Aim1: Why are CTCF
motifs associated with the TH17 program? Aim2: Why are TH17-associated genes accessible yet not active in
TREG cells? Aim3: Why do FOXP3+CD cells express prototypic TH17 cytokines? Upon conclusion, we will
understand the epigenetic pathways and 3D chromatin architecture spawning the FOXP3+CD cell and
mechanisms shaping their development and function. This contribution is significant as the FOXP3+CD cell is
expanded in the Crohn’s lesion, phenocopies TH17 cell which is implicated in Crohn’s disease (and other
inflammatory diseases), and represents an important epigenetic drug target for systemic or re-engineered
cellular therapy. There is general acknowledgement of risk of FOXP3+ TREG cells converting to pathogenic
FOXP3+TH17-like cells upon adoptive transfer in Crohn’s trials; yet, this project is the first to articulate both
signature and precise epigenetic events that regulate activation of the TH17 program in TREG cells.
Status | Active |
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Effective start/end date | 2/15/11 → 1/31/25 |
Funding
- National Institute of Allergy and Infectious Diseases: $397,500.00
- National Institute of Allergy and Infectious Diseases: $492,611.00
- National Institute of Allergy and Infectious Diseases: $498,524.00
- National Institute of Allergy and Infectious Diseases: $429,850.00
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