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 1

Enhanced gut-homing potential and depletion of circulating CD27+ Vδ2 T cells in CD.

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Enhanced gut-homing potential and depletion of circulating CD27+ Vδ2 T c...
(A) In patients with moderately active CD about to receive de novo AZA therapy (n = 12), flow-cytometric analysis of blood lymphocytes revealed a significant increase in the proportion of β7+ gut-homing cells within the CD3+ Vδ2 T cell population when compared with healthy controls (n = 26). (B) In a separate analysis of pediatric CD patients (mean age 13 years), we observed that the overall proportion of β7+ Vδ2 T cells in blood was comparable with adult CD patients (NS, not shown), but the CD45RA–CD27+ subset was selectively depleted compared with sex/age/ethnicity-matched IBS controls (*P < 0.001; n = 8 per group), while the subset distribution of conventional αβ T cells as defined by these markers was unaltered in CD (data not shown). (C) The CD27+ population of circulating Vδ2 T cells expressed significantly higher levels of β7 integrin than did any other Vδ2 T cell subset (*P < 0.05; n = 8), consistent with increased trafficking of these cells to the gut and a corresponding depletion from the blood in CD. (D) Example histograms showing integrin β7 expression levels in the different Vδ2 T cell subsets detected in blood from an IBS control (representative of n = 8). Significant differences between groups were determined by Mann-Whitney rank-sum test (A), or repeated-measures ANOVA (B and C).