NKp44

NKp44, also known as natural cytotoxicity receptor 2 (NCR2), is an activating receptor expressed on natural killer (NK) cells. It is one of the natural cytotoxicity receptors that enable NK cells to recognize virus-infected and transformed cells. NKp44 expression is upregulated when NK cells are activated, for example by cytokines such as interleukin-2 (IL-2) and interleukin-15 (IL-15). The receptor signals through association with the adaptor molecule DAP12, coordinating cytotoxic responses and cytokine production, including interferon-gamma (IFN-γ).

Ligands for NKp44 include influenza virus hemagglutinin and various cellular ligands present on tumor or infected cells. In some contexts, proliferating cell nuclear antigen (PCNA) exposed on the surface of certain tumor cells can bind NKp44 and inhibit NK cell activity, illustrating the receptor’s complex role in immune regulation.

NKp44 exists in multiple splice variants, with at least three isoforms described: NKp44-1, NKp44-2, and NKp44-3. The NKp44-1 isoform is associated with activating signaling, while NKp44-2 and NKp44-3 contain cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can dampen signaling in certain circumstances. The balance of isoform expression and ligand engagement contributes to the regulation of NK cell responses in health and disease.

In research and clinical contexts, NKp44 relevance spans cancer immunology and viral infections, where its expression and ligand interactions influence NK cell–mediated cytotoxicity and cytokine production. Ongoing studies aim to define the full spectrum of NKp44 ligands and the regulatory impact of its isoforms on NK cell function.