CD1-restricted recognition of exogenous and self-lipid antigens by duodenal γδ⁺ T lymphocytes

γδ T cells are present in the mucosal intestinal epithelia and secrete factors necessary to maintain tissue integrity. Ags recognized by these cells are poorly defined, although in mice non-classical MHC class I molecules have been implicated. Since MHC class I-like CD1 receptors are widely expressed at the surface of epithelial and dendritic intestinal cells and have the capacity to present lipid Ags to T cells, we hypothesized that these molecules might present autologous and/or exogenous phospholipids to intestinal γδ T lymphocytes. Intraepithelial T lymphocytes from normal human duodenal mucosal biopsies were cloned and exposed to natural and synthetic phospholipids using CD1a-, CD1b-, CD1c- or CD1d-transfected C1R lymphoblastoid or HeLa cell lines as APCs. Their cytolytic properties and regulatory cytokine secretion were also examined. Most clones obtained from duodenal mucosa (up to 70%) were TCRαβ⁺, and either CD4⁺ or CD8 ⁺, whereas 20% were CD4 CD8 (6 clones) or TCRγδ ⁺ (12 clones). A relevant percentage (up to 66%) of TCRγδ⁺ but few (<5%) TCRαβ⁺ T cell clones responded to synthetic and/or natural phospholipids presented by CD1 molecules, as measured by both [³H]thymidine incorporation and EL-4 release assays. A Th1-like cytolytic and functional activity along with the ability to secrete regulatory cytokines was observed in most phospholipid-specific γδ T cell clones. Thus, a substantial percentage of TCRγδ⁺ but few TCRαβ⁺ from human duodenal mucosa recognize exogenous phospholipids in a GD1-restricted fashion. This adaptive response could contribute to mucosal homeostasis, but could also favor the emergence of inflammatory or allergic intestinal diseases.