P061. Ileum versus colon: separate roles for gut dendritic cells in mucosal immune homeostasis and implications for ulcerative colitis
E. Mann1, D. Bernardo1, H. Omar Al-Hassi1, N. English1, J. Landy2, S. Peake2, R. Man2, G. Han Lee2, N. Yassin2, S. Knight1, A. Hart2, 1Imperial College London, United Kingdom, 2St. Mark's Hospital, United Kingdom
Gut dendritic cells (DC) maintain the balance between immunogenicity and tolerance at intestinal sites; dysregulation can result in ulcerative colitis (UC). DC are key in UC pathogenesis as drivers of effector T-cell responses, and imprint homing properties on T-cells. However, data on gut DC in humans is scarce, and murine data refers to the ileum or organised lymphoid tissues. We compared the function of human gut DC from the colon and ileum, to compare to our previous studies on gut DC in UC.
Healthy human DC were isolated from colonic and ileal biopsies (paired samples) and characterised by flow cytometry, co-cultured with allogeneic T-cells. Stimulated T-cells were characterised by flow cytometry.
Levels of DC activation marker CD40 were increased on DC from the ileum compared to the colon, but numbers of “tolerogenic” CD103+CCR7+ DC were reduced in the ileum. Both ileal and colonic DC imprinted gut-homing marker β7 on stimulated T-cells, but only ileal DC generated T-cells expressing small bowel-homing marker CCR9. Skin-homing markers CLA and CCR4 were enhanced on T-cells stimulated by ileal DC. Colonic DC generated CD25+FoxP3+IL-10+ regulatory T-cells and T-cells producing anti-inflammatory cytokine TGFβ, whilst ileal DC favoured inflammatory IFN γ-producing T-cells expressing Th1 transcription factor T-bet, alongside an enhanced overall T-cell stimulatory capacity.
We demonstrate for the first time, specific, functional differences between human colonic and ileal DC. Colonic DC exhibited a tolerogenic phenotype and generated regulatory T-cells, whilst ileal DC displayed an enhanced ability to prime inflammatory T-cell responses, possibly representing an evolutionary adaptation to the greater bacterial load in the colon. Our previous studies demonstrated increased gut DC activation in UC, enhanced gut DC stimulatory capacity for inflammatory, CCR9+ T-cells, loss of CD103+ DC from the UC gut and reduced DC-driven TGFβ production by T-cells. Taken with these results, this current study suggests colonic DC adopt “small-bowel DC-like” properties in UC, and provides an explanation for the occurrence of extra-intestinal manifestations of UC affecting the skin, given ileal DC enhance skin-homing capacity of T-cells. The local microenvironment shapes DC function; the dysregulated DC function in UC may be linked to changes in the colonic gut microbiota reported in UC.