All ETDs from UAB

Advisory Committee Chair

Robin G Lorenz

Advisory Committee Members

Charles O Elson

Selvarangan Ponnazhagan

Lesley E Smythies

Chad Steele

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Regulatory T cells (Treg) are necessary for the maintenance of immune homeostasis, and have been implicated in several autoimmune diseases, including inflammatory bowel disease (IBD). Most murine studies focusing on the function of Tregs have been done on the C57BL/6 or BALB/c background, creating a bias towards these two strains. In addition, it has been shown that C57BL/6 and BALB/c Tregs function in different manners. To further investigate potential strain differences in Treg phenotype and function, we chose to analyze FVB/N Tregs. Several differences were observed, including de-creased FVB/N Treg suppression in a non-cell contact dependent manner, decreased FVB/N and BALB/c Treg surface expression of glycoprotein A repetitions predominant (GARP) and latency associated peptide (LAP) and decreased Cste mRNA expression on C57BL/6 Tregs. In addition, BALB/c natural Tregs (nTregs) were more capable of main-taining Foxp3 expression, and C57BL/6 CD4+CD25- naïve T cells were more likely to be induced to express Foxp3 when exposed to TGF-ß and to become induced Tregs (iTregs). These data suggest there are genetic differences between the phentoype and function of Treg cells that should be taken into account in future Treg studies. The FVB.mdr1a-/- mouse, lacking the small molecule pump P-glycoprotein (P-gp), develops spontaneous T cell mediated colitis. In addition, MDR1 polymorphisms and P-gp deficiency in humans have been linked to the development of ulcerative colitis. We chose this model to investigate the role of Tregs in IBD development. Our studies demonstrated a significant decrease of Foxp3+ Tregs in the Peyer's patches and small in-testinal lamina propria of FVB.mdr1a-/- mice, which precedes spontaneous disease in these animals. We did not observe altered trafficking, apoptosis, or plasticity of FVB.mdr1a-/- Tregs. However, FVB.mdr1a-/- mice were unable to generate iTregs effectively, both in vitro and in vivo. Without the generation of iTregs, FVB.mdr1a-/- animals are more susceptible to intestinal inflammation. In concordance with our studies, the susceptibility of FVB.mdr1a-/- mice to colonic inflammation may influence the difference in Treg function between the two strains. The presence of the MDR1 polymorphism in the human population demonstrates the importance of understanding the function of Tregs in the IBD patient population.

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