Dedicated Immunosensing of Mouse Intestinal Epithelium Facilitated by Genetically Coupled Lectin-like Receptors

The integrity of the intestinal epithelium is constantly surveyed by innate-like, intraepithelial T lymphocytes (IELs). IELs are thought to act as ‘‘first-line’’ sentinels sensing the state of adjacent epithelial cells via both T-cell receptors and auxiliary receptors. The latter include C-type lectin-like receptors (CTLR) encoded in the natural killer gene complex (NKC) such as NKG2D.
We report fairly exclusive expression of the CTLR Nkrp1g by a subpopulation of mouse IELs enabling them to monitor the intestinal epithelium through ligation of the genetically coupled CTLR Clr-f, almost exclusively expressed on differentiated intestinal epithelial cells (IECs). As Clr-f expression strongly inhibits effector functions of Nkrp1g-expressing cells and is upregulated upon poly(I:C) challenge, Clr-f molecules may quench reactivity of Nkrp1g⁺ IELs towards the epithelial barrier. Of note, we also found that the orphan CTLR Clr-a, the closest Clr-f relative, is exclusively expressed by IECs. Using newly generated antibodies and in situ immunofluorescence, we localized Clr-a molecules in the small and large intestines showing that Clr-a and Clr-f are also highly related with regard to tissue expression. Altogether, we characterized genetically linked CTLR with an intestine-associated expression that apparently evolved to allow for a dedicated immunosurveillance of the mouse intestinal epithelium.