Human uterine NK cells express CD96/TACTILE under the regulation of IL-15 and TGFβ1

Abstract

Uterine natural killer (uNK) cells are a tissue-specific subset of innate lymphocytes with unique functions including the engagement with placenta-derived extra-villous trophoblast (EVT) cells. While several receptor-ligand pairs of this interaction have been identified, many remain poorly characterized. Here, we investigated the expression and regulation of nectin-like receptor CD96/TACTILE on human uNK cells, which recognizes ligands expressed by EVT cells. Using flow cytometry, we analysed NK cells from menstrual blood and from first- and second-trimester decidua, alongside peripheral blood cells used as reference. We identified a predominant exon 4-lacking splice variant of CD96 on uNK cells and found that CD96 is part of a broader set of receptors associated with NK cell tissue-residency regulated by IL-15 and TGFβ1. In vitro, IL-15 and canonical as well as non-canonical TGFβ1 signalling upregulate CD96 surface expression. Finally, redirected cross-linking assays showed no major effect of CD96 engagement on degranulation in decidual NK (dNK) cells. Taken together, these findings reveal that human uNK cells adapt to an IL-15- and TGFβ1-rich environment by shifting nectin-like receptor expression, with potential implications for dNK–EVT interactions during placentation.