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

Gamma-delta T cells are present in the mucosal intestinal epithelia and secrete factors necessary to maintain tissue integrity. Antigens recognized by these cells are poorly defined, although in mice non-classical MHC class I molecules have been implicated. Since MHC-I-like CD1 receptors are widely expressed at the surface of epithelial and dendritic intestinal cells and have the capacity to present lipid antigens to T cells, we hypothesized that these molecules might present autologous and/or exogenous phospholipids to intestinal gamma-delta 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 TcRalfa-beta+, and either CD4+ or CD8+, whereas 20% were CD4-CD8- (6 clones) or TcRgamma-delta (12 clones). A relevant percentage (up to 66%) of TcRgamma-delta but few (less than 5%) TcRalfa-beta+ T cell clones responded to synthetic and/or natural phospholipids presented by CD1 molecules, as measured by both 3H-thymidine incorporation and IL-4 release assays. A Th1-like cytolytic and functional activity, together with the ability to secrete regulatory cytokines was observed in most phospholipid-specific gamma-delta T cell clones. Thus, a substantial percentage of TcRgamma-delta+ but few TcRalfa-beta+ from human duodenal mucosa recognize exogenous phospholipids in a CD1-restricted fashion. This adaptive response could contribute to mucosal homeostasis, but could also favour the emergence of inflammatory or allergic intestinal diseases.