Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease
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
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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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 2

Intestinal Vδ2 T cells in CD patients express CD27 and incorporate both CD103– and CD103+ subsets.

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Intestinal Vδ2 T cells in CD patients express CD27 and incorporate both ...
(A) Representative examples of Vδ2 T cell subset distribution in blood from an IBS control (HC) and a patient with CD showing selective depletion of the CD45RA–CD27+ subset in CD (each plot is representative of n = 8 independent experiments, and both display an equal number of cells). (B) Intestinal biopsy tissue from patients with new diagnoses of CD contained a distinct population of Vδ2 T cells that displayed a CD27+ phenotype analogous to that of the cells depleted from peripheral blood. (C) Mucosal Vδ2 T cells in CD patients included both CD103– and CD103+ subsets in proportions comparable to those present in the healthy intestine. Shown is an example flow-cytometry analysis of colonic biopsy tissue after extensive removal of the epithelium and showing positive identification of Vδ2 T cells (thus excluding Vδ1 T cells) among the egressed leukocytes in an 18-year-old patient with active CD (B; representative of n = 11 CD patients), as well as grouped data showing Vδ2 T cell subset balance in multiple individuals (C; n = 11 CD patients, n = 9 healthy controls; comparison by t test).