CHARACTERIZATION AND FUNCTIONAL RELEVANCE OF A NEWLY DISCLOSED SUBSET OF NCRPOS GAMMA/DELTA T CELLS NATURALLY RESIDENT IN HUMAN INTESTINE.

gd T cells display a broad array of anti-tumor functions by combining their rapid innate-like cytotoxic response with secretion of immunoregulatory cytokines, such as IFN-g. Intestinal intraepithelial lymphocytes (IELs) are particularly enriched of gd T cells; however, data regarding specific gd T subsets in homeostatic and pathological conditions of human intestine are lacking. Therefore, by a multiparametric flow cytometry approach, we identified a novel human specific intestinal gd IELs population constitutively expressing Natural Killer (NK) cell-specific cytotoxic receptors (NCRs), in association with several immune-regulating molecules including: CD56, CD8, CD28, NKG2C and NKG2D. Expression of NKp46 was restricted to Vd1pos (but not Vd2pos) gd IELs and proved to be the dominant NCR compared to the lower level of NKp44 and almost undetectable expression of NKp30. The NKp46pos/Vd1pos subset has gut-specific residency rather than systemic tissue distribution since no other analyzed human specimens, such as liver or lymph nodes showed expression of NCRs on gd T cells. Moreover, we found no immune counterpart of the human NKp46pos/gdT cell subset in different anatomical sites of BALB/c or C57BL/6 mouse strains. NKp46pos IELs reflects functionally higher anti-tumor activity compared to their NKp46negcounterpart as evaluated by increased synthesis of both granzyme B (GRZ-B) and IFN-g. The specific NKp46pos phenotype is a feature of IL2/IL15-induced human thymic gd T precursors that consecutively acquire anti-tumor activity. In addition, elevated occurrence of the intestinal NKp46pos/Vd1pos T cell subset correlates with significantly lower tumor progression in patients with colorectal carcinoma (CRC). On the other hand, the tumor microenvironment negatively controls the incidence of both Vd1 and NKp46pos subset compared to the specific intestinal intraepithelial anatomical site. Collectively, this work identifies a novel human gut-specific differentiated NKp46pos phenotype with multifunctional immunoregulatory and cytotoxic anti-tumor activity, and with the potential to represent a prognostic marker of human CRC pathology.