Human intestinal Vδ1⁺ T lymphocytes recognize tumor cells of epithelial origin

γδ T cells can be grouped into discrete subsets based upon their expression of T cell receptor (TCR) variable (V) region families, their tissue distribution, and their specificity. Vδ2 ⁺ T cells constitute the majority of γδ T cells in peripheral blood whereas Vδ1⁺ T cells reside preferentially in skin epithelium and in the intestine. γδ T cells are envisioned as first line host defense mechanisms capable of providing a source of immune effector T cells and inmunomodulating cytokines such as interleukin (IL) 4 or interferon (IFN) γ. We describe here the fine specificity of three distinct γδ⁺ tumor-infiltrating lymphocytes (TIL) obtained from patients with primary or metastatic colorectal cancer, that could be readily expanded in vitro in the presence of IL-1β and IL-7. Irrespective of donor, these individual γδ T cells exhibited a similar pattern of reactivity defined by recognition of autologous and allogeneic colorectal cancer cells, renal cell cancer, pancreatic cancer, and a freshly isolated explant from human intestine as measured by cytolytic T cell responses and by IFN-γ release. In contrast, tumors of alternate histologies were not lysed, including lung cancer, squamous cell cancer, as well as the naturally/lymphocyte-activated killer cell-sensitive hematopoietic cell lines T2, C1R, or Daudi. The cell line K562 was only poorly lysed when compared with colorectal cancer targets. Target cell reactivity mediated by Vδ1⁺ T cells was partially blocked with Abs directed against the TCR, the β2 or β7 integrin chains, or fibronectin receptor. Marker analysis using flow cytometry revealed that all three γδ T cell lines exhibit a similar phenotype. Analysis of the γδ TCR junctional suggested exclusive usage of the Vδ1/Dδ3/Jδ1 TCR segments with extensive (≤29 bp) N/P region diversity. T cell recognition of target cells did not appear to be major histocompatibility complex restricted or to be correlated with target cell expression of heat-shock proteins. Based on the ability of some epithelial tumors, including colorectal, pancreatic, and renal cell cancers to effectively cold target inhibit the lysis of colorectal cancer cell lines by these Vδ1⁺ T cell lines, we stiffest that intestinal Vδ1⁺ T cells are capable of recognizing cell surface Ag(s) shared by tumors of epithelial origin.