Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a V gamma 9V delta 2 T cell receptor (V delta 2 T cells) and mediate host protection against microbial infections and malignancies. V delta 2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed V delta 2 T cell phenotype and function by flow cytometry in blood and intestinal tissue from Crohn's disease patients (CD patients) and healthy controls. Blood from CD patients included an increased percentage of gut-tropic integrin beta 7-expressing V delta 2 T cells, while "Th1-committed" CD27-expressing V delta 2 T cells were selectively depleted. A corresponding population of CD27(+) V delta 2 T cells was present in mucosal biopsies from CD patients and produced elevated levels of TNF alpha compared with controls. In colonic mucosa from CD patients, V delta 2 T cell production of TNFa was reduced by pharmacological blockade of retinoic acid receptor-a (RAR alpha) signaling, indicating that dietary vitamin metabolites can influence V delta 2 T cell function in inflamed intestine. V delta 2 T cells were ablated in blood and tissue from CD patients receiving azathioprine (AZA) therapy, and posttreatment V delta 2 T cell recovery correlated with time since drug withdrawal and inversely correlated with patient age. These results indicate that human V delta 2 T cells exert proinflammatory effects in CD that are modified by dietary vitamin metabolites and ablated by AZA therapy, which may help resolve intestinal inflammation but could increase malignancy risk by impairing systemic tumor surveillance.