Flt3 ligand expands CD103⁺ dendritic cells and FoxP3⁺ T regulatory cells, and attenuates Crohn's-like murine ileitis.

Abstract

UNLABELLED:

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 CX(3)CR1 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:

CD11c(Hi)/MHCII(+) MP accumulated in inflamed ilea, predominantly mediated by expansion of the CX(3)CR1(+) 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.

• Authors: Colm B Collins, Carol M Aherne, Eóin N McNamee, Matthew D P Lebsack, Holger Eltzschig, Paul Jedlicka, Jesús Rivera-Nieves
• Journal: Gut (Gut) Vol. 61 Issue 8 Pg. 1154-62 (Aug 2012) ISSN: 1468-3288 [Electronic] England
• PMID: 22068168 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, CD
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Integrin alpha Chains
• alpha E integrins
• RNA
• Flt3 protein, mouse
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Antigens, CD (biosynthesis, genetics)
• Crohn Disease (drug therapy, genetics, immunology)
• Dendritic Cells (immunology, pathology)
• Disease Models, Animal
• Flow Cytometry
• Forkhead Transcription Factors (biosynthesis, genetics)
• Gene Expression Regulation
• Ileitis (drug therapy, genetics, immunology)
• Ileum (immunology, metabolism, pathology)
• Integrin alpha Chains (biosynthesis, genetics)
• Intestinal Mucosa (immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• RNA (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes, Regulatory (immunology, pathology)
• Treatment Outcome
• fms-Like Tyrosine Kinase 3 (pharmacology)