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Published on: December 16, 2021
Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis
S M Tanner1, E M Staley, R G Lorenz
1Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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.
Insights
P-glycoprotein (P-gp) deficiency in mice reduces regulatory T cells (Tregs) crucial for gut health. This occurs because P-gp deficiency impairs the development of induced Tregs, potentially impacting inflammatory bowel disease.
Area of Science:
- Immunology
- Gastroenterology
Background:
- The FVB.mdr1a(-/-) mouse model lacks P-glycoprotein (P-gp), a key efflux pump.
- P-gp deficiency and MDR1 gene variations are linked to human ulcerative colitis.
- Regulatory T cells (Tregs) play a vital role in maintaining intestinal immune homeostasis.
Purpose of the Study:
- To investigate the impact of P-gp deficiency on Treg populations in the gut.
- To elucidate the mechanisms underlying altered Treg levels in P-gp deficient mice.
- To explore the potential role of P-gp in inflammatory bowel disease pathogenesis.
Main Methods:
- Comparison of Treg populations in wild-type and P-gp deficient (FVB.mdr1a(-/-)) mice.
- Assessment of Treg apoptosis, trafficking, and plasticity.
- In vitro studies of induced Treg (iTreg) development using TGF-β.
- Adoptive transfer experiments into immunodeficient recipients.
Main Results:
- P-gp deficient mice exhibited significantly lower levels of Foxp3(+) Tregs in the intestinal lamina propria.
- The reduction in Tregs was not attributed to increased apoptosis, altered trafficking, or plasticity.
- P-gp deficiency impaired the in vitro development of iTregs from naive T cells upon TGF-β stimulation.
- TGF-β stimulation in P-gp deficient cells resulted in a shift towards IL-17(+)CD4(+) T cells instead of Tregs.
- Adoptive transfer confirmed impaired iTreg development in P-gp deficient recipients.
Conclusions:
- P-gp deficiency restricts the development of induced Tregs, leading to decreased Treg numbers in the intestine.
- This impaired iTreg development represents a novel mechanism potentially contributing to inflammatory bowel disease.
- Further investigation into this mechanism in human patients with MDR1 polymorphisms is warranted.
