title: Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis.
abstract: The FVB.mdr1a(-/-) mouse, lacking the small molecule pump P-glycoprotein (P-gp), is a commonly used model for the study of 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 now demonstrate that mice with P-gp deficiency have decreased levels of Foxp3(+) regulatory T cells (Tregs) in the intestinal lamina propria. This decrease is not due to either increased Treg apoptosis, altered Treg trafficking, or enhanced Treg plasticity to become Foxp3(+)IL-17(+) cells. Instead, P-gp deficiency appears to restrict the development of induced Treg cells (iTregs), as fewer Foxp3(+) iTregs developed from naive FVB.mdr1a(-/-) T cells both upon transforming growth factor-β (TGF-β) treatment in vitro and after adoptive transfer into FVB.rag2(-/-) recipients. Rather, in vitro TGF-β treatment results in a IL-17(+)CD4(+) T cell. This failure of iTregs to develop explains the decrease in Foxp3(+) Tregs in the FVB.mdr1a(-/-) intestine, representing a need to investigate this novel disease mechanism in human inflammatory bowel disease patients with MDR1 polymorphisms.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Tanner
authors.forename: E M
authors.initials: EM
authors.lastname: Staley
authors.forename: R G
authors.initials: RG
authors.lastname: Lorenz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta