P066. Human intestinal Vδ2+ T-cells promote mucosal inflammation in Crohn's disease and are selectively ablated by azathioprine therapy
N. McCarthy1, C. Hedin1, Z. Bashir1, A. Vossenkämper1, E. Giles1, T. Sanders1, K. Whelan2, T. MacDonald1, J. Lindsay3, A. Stagg1, 1Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Centre for Immunology and Infectious Disease, The Blizard Institute, London, United Kingdom, 2King's College London, School of Medicine, Diabetes and Nutritional Sciences Division, London, United Kingdom, 3Digestive Diseases Clinical Academic Unit, Barts and The London School of Medicine, The Royal London Hospital, London, United Kingdom
Tumor-derived and microbial phosphoantigens specifically activate Vγ9Vδ2+ (Vδ2)T-cells which are found only in humans and higher primates. We have demonstrated that Vδ2T-cells populate the human intestinal mucosa and enhance inflammatory responses by conventional colonic T-cells, so we hypothesized that Vδ2T-cells promote pathological gut inflammation in Crohn's disease (CD).
Cell suspensions prepared from peripheral blood and intestinal biopsies were stimulated with HDMAPP phosphoantigen and analyzed by flow-cytometry.
Vδ2T-cells up-regulate the expression of gut-homing integrin α4β7 upon phosphoantigen stimulation in vitro, and circulating Vδ2T-cells in CD patients contained an elevated proportion of β7+ cells (CD median 80.8%, controls 64.9%; p = 0.010), and CD69+ cells (p = 0.006) that correlated with reduced Vδ2T-cell frequency (p = 0.0018), suggesting increased activation/trafficking to the gut. Intestinal biopsies from both CD patients and controls contained CD103− and CD103+ Vδ2T-cells that produced IFNγ and TNFα, but the influence of Vδ2T-cell subset balance on IFNγ production by mucosal αβ T-cells was disrupted in CD. Blood Vδ2T-cells rarely expressed CD103, but this integrin was significantly induced upon HDMAPP activation in the presence of TGF-β1, suggesting that TGF may regulate Vδ2T-cell mucosal phenotype. There was an extensive, selective loss of Vδ2T-cells in blood from CD patients receiving azathioprine therapy (p < 0.001), and azathioprine impaired proliferation and cytokine production by intestinal Vδ2T-cells in vitro.
These data demonstrate that human intestinal Vδ2T-cells exert pro-inflammatory effects in CD that are ablated by azathioprine therapy, which may help to resolve intestinal inflammation, but could also confer increased risk of malignancy due to loss of tumor surveillance by Vδ2T-cells in blood.