Inhibitory receptors specific for MHC class I educate murine NK cells but not CD8αα intestinal intraepithelial T lymphocytes

Abstract

The engagement of inhibitory receptors specific for major histocompatibility complex class I (MHC-I) molecules educates natural killer (NK) cells, meaning the improvement of the response of activation receptors to subsequent stimulation. It is not known whether inhibitory MHC-I receptors educate only NK cells or whether they improve the responsiveness of all cell types, which express them. To address this issue, we analyzed the expression of inhibitory MHC-I receptors on intestinal intraepithelial lymphocytes (iIELs) and show that T-cell receptor (TCR)-CD8 iIELs express multiple inhibitory receptors specific for MHC-I molecules, including CD94/NKG2A, Ly49A, and Ly49G2. However, the presence of MHC-I ligand for these receptors did not improve the response of iIELs to activation via the TCR. The absence of iIEL education by MHC-I receptors was not related to a lack of inhibitory function of these receptors in iIELs and a failure of these receptors to couple to the TCR. Thus, unlike NK cells, iIELs do not undergo an MHC-I-guided education process. These data suggest that education is an NK cell-specific function of inhibitory MHC-I receptors. (Blood. 2011; 118(2):339-347)

CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells

“…18 However, in mice, intraepithelial T cells were not educated by interactions with self-MHC class I molecules, suggesting that such education is an NK cell-specific process. 37 Because our studies suggested a random distribution of selfand nonself-KIRs on CD8 T cells, we set out to determine whether the specificity of the expressed KIRs had any functional consequences on CD8 T cells in humans. Ideally, such experiments should be performed by physiologic stimulation of the TCR with MHC/peptide complexes.…”

“…Furthermore, the general hyporesponsiveness of human CD8 T cells that express self-specific KIRs supports the finding in mice that, unlike NK cells, CD8 T cells are not functionally educated by interactions with self-MHC class I molecules. 18,37 The nearly monoclonal TCR V␤ chain distribution on KIR ϩ CD8 T cells could indicate that KIR repertoires are shaped when CD8 T cells undergo clonal expansion in response to pathogenic challenges or to autoantigens. Previous studies have attempted to delineate the TCR specificity of KIR ϩ CD8 T cells.…”

DifferentialLy49eExpression Pathways in Resting versus TCR-Activated Intraepithelial γδ T Cells

“…TCRgd + iIELs express low levels of several Ly49 receptors, of which Ly49E is the most abundant (14,15). In contrast to DETCs, freshly isolated iIELs display a bimodal Ly49E expression with both Ly49E low and Ly49E high cells ( Fig.…”

“…DETCs and iIELs are both characterized by the expression of several NK receptors, as follows: 2B4 (9, 10), NKG2A/C/E (11), NKG2D (12), and/or members of the Ly49 receptor family (9,11,(13)(14)(15). Among the entire Ly49 receptor family, Ly49E is the only Ly49 member expressed by fetal thymic Vg3 T cells and adult skin DETCs (11), and it is the most abundantly expressed member on TCRgd + iIELs (14).…”

“…Among the entire Ly49 receptor family, Ly49E is the only Ly49 member expressed by fetal thymic Vg3 T cells and adult skin DETCs (11), and it is the most abundantly expressed member on TCRgd + iIELs (14). Whereas the activating NKG2D and 2B4 NK receptors and the inhibitory NKG2A NK receptor are expressed by the majority of DETCs and/or iIELs (9)(10)(11)(12), Ly49E is expressed by only 20 and 10% of DETCs and TCRgd + iIELs, respectively (11,(13)(14)(15). Remarkably, whereas only 20% of DETCs express Ly49E, 60% of their fetal thymic Vg3 + precursors bear the receptor (11).…”