Flt3 ligand expands CD103+ dendritic cells and FoxP3+ T regulatory cells, and attenuates Crohn's-like murine ileitis
- Colm B Collins1,
- Carol M Aherne2,
- Eóin N McNamee1,
- Matthew D P Lebsack1,
- Holger Eltzschig2,
- Paul Jedlicka3,
- Jesús Rivera-Nieves4
- 1Mucosal Inflammation Program, Department of Internal Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- 2Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- 3Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- 4Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California at San Diego, San Diego, California, USA
- Correspondence to Dr Jesús Rivera-Nieves, 9500 Gilman Drive, Building UC 303, Room 211, San Diego, CA 92093-0063, USA;
Contributors All authors contributed to the design, data generation, manuscript preparation and revisions.
- Revised 5 October 2011
- Accepted 6 October 2011
- Published Online First 7 November 2011
Background Imprinting an effector or regulatory phenotype on naïve T cells requires education at induction sites by dendritic cells (DC).
Objectives To analyse the effect of inflammation on the frequency of mononuclear phagocytes (MP) and the effect of altering their frequency by administration of Flt3-L in chronic ileitis.
Methods Using a tumour necrosis factor (TNF) driven model of ileitis (ie, TNFΔARE) that recapitulates many features of Crohn's disease (CD), dynamic changes in the frequency and functional state of MP within the inflamed ileum were assessed by flow cytometry, immunofluorescence and real-time reverse-transcription PCR and by generating CX3CR1 GFP-reporter TNFΔARE mice. The effect of Flt3-L supplementation on the severity of ileitis, and the frequency of CD103+ DC and of FoxP3+ regulatory T cells was also studied in TNFΔARE mice.
Results CD11cHi/MHCII+ MP accumulated in inflamed ilea, predominantly mediated by expansion of the CX3CR1+ MP subpopulation. This coincided with a decreased pro-regulatory CD103+ DC. The phenotype of these MP was that of activated cells, as they expressed increased CD80 and CD86 on their surface. Flt3-ligand administration resulted in a preferential expansion of CD103+ DC that attenuated the severity of ileitis in 20-week-old TNFΔARE mice, mediated by increased CD4+/CD25+/FoxP3+ regulatory T cells.
Conclusions Results support a role for Flt3-L as a potential therapeutic agent in Crohn's-like ileitis.
Funding This project was funded by grants from the NIH/NIDDK USPHS DK080212-01, the Crohn's and Colitis Foundation of America (CCFA) Senior Research Award 2826, and US Veteran's Administration BLR&D Merit Review Award 1I01BX001051 to JR-N and the CCFA 2652 to CBC.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data will be shared with interested scientists.