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
View: Text | PDF
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

×

Figure 7

Post-AZA recovery of blood Vδ2 T cells is influenced by patient age and time elapsed since drug withdrawal.

Options: View larger image (or click on image) Download as PowerPoint
Post-AZA recovery of blood Vδ2 T cells is influenced by patient age and ...
(A) Cross-sectional study of CD patients previously treated with AZA for >1 year but not receiving thiopurine therapy at the time of sampling (ex-AZA; n = 10). Evidence of blood Vδ2 T cell recovery was observed in 5 of 10 ex-AZA CD patients (recovery threshold Q1 defined as the 25th percentile of Vδ2 T cell frequency in AZA-naive CD patients), but not in any of the CD patients on concurrent AZA therapy (AZA+; n = 17). Fisher exact test was used to assess Vδ2 T cell recovery after AZA withdrawal. (B and C) Blood Vδ2 T cell frequency in the ex-AZA CD patients was positively correlated with time elapsed since drug withdrawal (B; n = 9), and was inversely correlated with patient age (C; n = 13). Correlations were assessed using Pearson product-moment.