Expression of a Novel Immune Receptor on Lymphoid Tissue Inducer-Derived Cells: A Candidate Murine Homologue Of the Human NKp44 Receptor

Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that efficiently kill virus-infected and transformed cells. In addition, they are an important innate source of the cytokine interferon (IFN)-gamma. NK cell activation is determined by the input of signals from inhibitory and stimulatory immunoreceptors. The human NKp44 receptor is an activating NK cell receptor and was first identified on human CD56 + NK cells and has traditionally been regarded as an NK cell-specific marker. It was initially observed that NKp44 was not constitutively expressed on NK cells but is upregulated on interleukin (IL-) 2-stimulated NK cells. Though the expression of NKp44 is low on CD56+ cells in the peripheral blood, examination of CD56+ cells found in human tonsils revealed that a good proportion of these cells expressed the NKp44 receptor. More interestingly, these NKp44+CD56+ cells have the ability to produce the cytokine IL-22 and also express the transcription factor RORgammat.;In light of newly available data, it is becoming increasingly clear that these IL-22 producing NKp44+ cells may not be of the NK cell lineage but are cells that are derived from lymphoid tissue-inducer (LTi) cells. Thus, though NKp44 has long been regarded as an NK cell-specific marker, it is becoming apparent that this receptor also marks a unique subset of IL-22-producing cells that co-express RORgammat and may be derived from a lineage that is distinct from conventional NK cells.;In the search for the mouse homologue of the human NKp44 receptor, a gene was located that resides in the exact syntenic locus of mouse chromosome 17 as the gene encoding the human NKp44 receptor. We have tentatively called this gene Ncr2. Analysis of the protein encoded by this gene (Ncr2) showed that it is structurally similar to human NKp44 and utilizes the same signaling adapter molecule as the NKp44 receptor. Furthermore, studying the expression of Ncr2 on lymphocyte subsets, the receptor was observed to be narrowly expressed on a small subset of cells residing in the secondary lymphoid organs of mice that also expresses the transcription factor RORgammat and is able to produce the cytokine IL-22. These cells are positive for NK cell-specific markers and can be demonstrated to arise from LTi cells and are developmentally distinct from conventional NK cells.;The presence of this newly described receptor on murine NKR+ LTi-derived cells, and other similarities between Ncr2 and the human NKp44 receptor, make it a prime candidate for being the murine homolog of NKp44.