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P054 CD103+SIRPα+ DC are specifically decreased in the inflamed colon from patients with ulcerative colitis but not with Crohn’s disease

D. Bernardo*1, S. Fernandez-Tome1, A. C. Marin1, L. Ortega-Moreno1, A. Montalban-Arques1, I. Mora-Gutierrez1, A. Fiz-Lopez1, F. Casals1, J. A. Moreno-Monteagudo1, T. Alvarez-Male1, V. Martin1, I. Becerro1, M. J. Casanova1, C. Santander1, M. Chaparro1, J. P. Gisbert1

1Insittuto Investigación Princesa, Madrid, Spain

Background

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammation of the human gastrointestinal (GI) tract. Intestinal dendritic cells (DC) are essential to maintain the balance between immunity against pathogens and tolerance towards nutrients and commensals. However, there is not much information about DC composition in the human GI tract both in health and IBD.

Methods

Human GI biopsies were obtained from healthy controls and IBD patients (including UC and CD; both active and quiescent). Tissue was disaggregated and lamina propria mononuclear cells (LPMC) characterised by flow cytometry.

Results

Human intestinal DC were identified within singlet viable leucocytes as CD14-CD64-HLA-DR+CD11c+. Type 1 DC were defined as CD103+SIRPα- while type 2 DC were identified as SIRPα+ and further divided into subsets based on the expression of CD103. The proportion of total DC displayed a gradient throughout the healthy human gut as it was higher in the colon (either distal or proximal) compared with the ileum. DC proportion was further decreased in the duodenum. Type 1 (minority) and type 2 (majority) conventional DC did not change their proportion throughout the healthy gut. However, CD103+SIRPα+ DC were the main subset in the duodenum as opposed to CD103-SIRPα+ DC which were predominant in the colon and the ileum. Compared with their CD103-SIRPα+ type 2 counterparts, CD103+SIRPα+ had higher levels of HLA-DR, CD40, CD86, CCR7, CD137L, ICOSL and PD-L1. CD103+SIRPα+ were also more phagocytic and had lower expression of blood-related markers like CLA and CCR2, suggesting that they are derived from CD103-SIRPα+ DC following mucosal conditioning. Indeed, CD103+SIRPα+ numbers were increased following LPMC culture, although this process was reverted in the presence of pro-inflammatory LPS. CD103+SIRPα+ DC displayed an enhanced production of IL-10, both in resting conditions and in the presence of LPS. In IBD, type 2 DC constitutively displayed lower expression of SIRPα irrespectively of IBD-type (CD or UC) or condition (active or quiescent). Nevertheless, the inflamed colon from UC patients, but not from CD, specifically displayed lower numbers of tolerogenic CD103+SIRPα+ DC. These results were in agreement with the colonic cytokine milieu, which was much more pro-inflammatory in UC patients compared with CD.

Conclusion

Tolerogenic PD-L1 expression and IL-10 production was associated with CD103+SIRPα+ DC, confirming therefore their tolerogenic phenotype. Human colonic DC from IBD patients constitutively display lower levels of SIRPα. The specific reduction of CD103+SIRPα+ DC in the inflamed mucosa from UC, but not CD, suggests the presence of different pathogenic mechanisms occurring in IBD.