Phenotypic and Functional Characterization of Human TCRγδ+ Intestinal Intraepithelial Lymphocytes

Abstract

Intestinal intraepithelial lymphocytes (IEL) appear to represent a peculiar set of immune cells compartmentalized at the interface between the organism and the external environment. In previous studies we observed that within human IEL TCR-τ/δ T cells represent a major fraction that predominantly express the CD8 molecule and preferentially uses the V-δ-1 gene segment. Thus these data suggested a preferential accumulation/homing of CD8+ V-δ-1⁺ IEL within the human intestinal epithelium. However, to date the functional role of these cells with regard to immune regulation at this most critical immunological site is poorly understood. In this study, the cytotoxic potential and proliferative capacity of human IEL in response to mitogenic stimuli has been characterized with respect to IEL T cell receptor type and TCR-τ/δ variable gene segment usage as determined by flowcytometry. The frequeny of TCR-1+ IEL expressing both CD56 and CD16 which are considered to be NK-cell markers was found to be much higher (38.9±12.4%) than within intestinal lamina propria lympmocytes (LPL) (9.1±4.8%) or peripheral blood lymphocytes (PBL) (6.4±3.3%). In contrast, the fractions of CD16⁻ CD56⁺ cells within IEL, LPL and PBL were comparable. Surprisingly, IEL mediated NK-cell activity (K562 lysis) was virtually absent whereas within PBL it was within the normal range. Furthermore, in cytotoxicity assays employing ⁵¹ Cr-labeled OKT3 hybridoma cells and P815 cells as targets, the cytotoxic potential of IEL was much lower than that of PBL. Finally, only a minority (41.9±4.4%) of TCR-τ/δ IEL were CD5+ whereas the fraction of CD5⁺ TCR-τ/δ LPL and TCR-τ/δ PBL were 69.8±12.8% and 82.8±8.4%, respectively. The latter finding suggests an extrathymic pathway of differentiation for TCR-τ/δ+ IEL. Taken together, our data suport the notion that human IEL represent a functionally, phenotypically and ontogenetically distinct population of cells that may regulate the local mucosal response by mechanisms different from those described for other lymphoid tissues such as peripheral lymph nodes or the peripheral blood.