title: 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.forename: Neil E
authors.initials: NE
authors.lastname: McCarthy
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Hedin
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Sanders
authors.forename: Protima
authors.initials: P
authors.lastname: Amon
authors.forename: Inva
authors.initials: I
authors.lastname: Hoti
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Ayada
authors.forename: Vidya
authors.initials: V
authors.lastname: Baji
authors.forename: Edward M
authors.initials: EM
authors.lastname: Giles
authors.forename: Martha
authors.initials: M
authors.lastname: Wildemann
authors.forename: Zora
authors.initials: Z
authors.lastname: Bashir
authors.forename: Kevin
authors.initials: K
authors.lastname: Whelan
authors.forename: Ian
authors.initials: I
authors.lastname: Sanderson
authors.forename: James O
authors.initials: JO
authors.lastname: Lindsay
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Stagg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D018168:Receptors, Retinoic Acid / Q000276:immunology; D000072482:Retinoic Acid Receptor alpha; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; C000607071:RARA protein, human; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014409:Tumor Necrosis Factor-alpha; D001379:Azathioprine