Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease
Neil E. McCarthy, … , James O. Lindsay, Andrew J. Stagg
Neil E. McCarthy, … , James O. Lindsay, Andrew J. Stagg
Published July 13, 2015
Citation Information: J Clin Invest. 2015;125(8):3215-3225. https://doi.org/10.1172/JCI80840.
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Research Article Immunology

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

Abstract

Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a Vγ9Vδ2 T cell receptor (Vδ2 T cells) and mediate host protection against microbial infections and malignancies. Vδ2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed Vδ2 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 β7–expressing Vδ2 T cells, while “Th1-committed” CD27-expressing Vδ2 T cells were selectively depleted. A corresponding population of CD27+ Vδ2 T cells was present in mucosal biopsies from CD patients and produced elevated levels of TNFα compared with controls. In colonic mucosa from CD patients, Vδ2 T cell production of TNFα was reduced by pharmacological blockade of retinoic acid receptor-α (RARα) signaling, indicating that dietary vitamin metabolites can influence Vδ2 T cell function in inflamed intestine. Vδ2 T cells were ablated in blood and tissue from CD patients receiving azathioprine (AZA) therapy, and posttreatment Vδ2 T cell recovery correlated with time since drug withdrawal and inversely correlated with patient age. These results indicate that human Vδ2 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.

Authors

Neil E. McCarthy, Charlotte R. Hedin, Theodore J. Sanders, Protima Amon, Inva Hoti, Ibrahim Ayada, Vidya Baji, Edward M. Giles, Martha Wildemann, Zora Bashir, Kevin Whelan, Ian Sanderson, James O. Lindsay, Andrew J. Stagg

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Figure 6

Activation and depletion of Vδ2 T cells in AZA-treated CD.

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Activation and depletion of Vδ2 T cells in AZA-treated CD. (A–B) An anal...
(A–B) An analysis of CD patients with inactive disease (CDAI < 150; n = 19) indicated that the proportion of CD69+-activated Vδ2 T cells in the circulation was significantly enhanced compared with healthy volunteers (n = 25) (A) and also correlated with reduced cell frequency in blood (B). These data suggested that Vδ2 T cell activation and recruitment to the gut might contribute to loss of these cells from the circulation in CD. (C and D) In a cross-sectional study of AZA-treated CD patients (n = 27), ablation of circulating Vδ2 T cells was observed after >1 year continuous therapy (C) and longitudinal followup analyses confirmed a progressive loss of Vδ2 T cells with rapid onset after commencing AZA treatment (D; mean ± SEM of n = 3–5 CD patients per time point). CD patients and control groups were compared using unpaired t tests. Correlations were assessed using Spearman rank tests.