ICMI 2015

T.58 Cumulative Risk Variant SNPs in ATG16L1 Locus are Associated with Reduced Ability of Salmonella Infected Dendritic Cells to Generate Autologous Bacterial-Specific Foxp3+ Regulatory T (Treg) cells

Thursday, July 16, 2015
Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)
Aito Ueno, PhD , University of Calgary, Calgary, AB, Canada
Humberto Jijon, MD PhD , University of Calgary, Calgary, AB, Canada
Ronald Chan, MSc , University of Calgary, Calgary, AB, Canada
Subrata Ghosh, MD , University of Calgary, Calgary, AB, Canada
Atg16l1 SNPs may associate with Crohn’s disease(CD) via impaired autophagy and bacterial clearance resulting in compromised bacterial antigen presentation by dendritic cells(DC). We hypothesize that immune-function modulation results from the cumulative effects of several SNP variants rather than by a single SNP of atg16l1. Our aim was to assess whether cumulative SNPs are associated with changes in the ability of DC to generate bacterial-specific T cell subsets upon in vitro bacterial infection.

Genotypes of CD and healthy controls (HC) were analyzed using the Goldengate® assay. Individuals(13 CD and 11 HC) with homozygous in IL-23R(rs11209026,R381G) and wildtype in NOD2, PTPN22 and IRGM were enrolled in this study.  Monocyte-derived DC were differentiated from peripheral blood of the study participants using IL-4/GM-CSF and infected with Salmonella Typhimurium for 24 hours. The infected DC were co-cultured with autologous T cells for an additional 7-days and T cell polarization assessed using FACS.

Participants were categorized into 3 groups based on genotype at atg16l1 locus:  H1-all heterozygous, H2-homozygous in 2 SNPs(rs12994997 and s2241880,T300A) and wildtype in other 3 SNPs (rs13391356, rs2289472, and rs10192702), and H3-the reversed case of H2. No individuals with all homozygous nor all wildtype were found in this study.  Among T cell subsets, Foxp3+ Treg were significantly decreased in the total cohort with H3 and CD patients with H3 compared to those with H1. This suggests that reduced bacterial-specific Treg generation is not disease specific, but cumulative risk variants in atg16l1 locus are associated with reduced ability to generate Foxp3+ (Treg) cells.