A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44

Natural killer (NK) cells can recognize virus-infected and stressed cells 1 using activating and inhibitory receptors, many of which interact with HLA class I. Although early studies also suggested a functional impact of HLA class II on NK cell activity 2 , 3 , the NK cell receptors that specifically recognize HLA class II molecules have never been identified. We investigated whether two major families of NK cell receptors, killer-cell immunoglobulin-like receptors (KIRs) and natural cytotoxicity receptors (NCRs), contained receptors that bound to HLA class II, and identified a direct interaction between the NK cell receptor NKp44 and a subset of HLA-DP molecules, including HLA-DP401, one of the most frequent class II allotypes in white populations 4 . Using NKp44ζ + reporter cells and primary human NKp44 + NK cells, we demonstrated that interactions between NKp44 and HLA-DP401 trigger functional NK cell responses. This interaction between a subset of HLA-DP molecules and NKp44 implicates HLA class II as a component of the innate immune response, much like HLA class I. It also provides a potential mechanism for the described associations between HLA-DP subtypes and several disease outcomes, including hepatitis B virus infection 5 – 7 , graft-versus-host disease 8 and inflammatory bowel disease 9 , 10 . NK cells recognize class I and stress-associated ligands. Altfeld and colleagues identify the NK cell receptor NKp44 as directly interacting with the class II HLA-DP in a partially peptide-dependent manner and with functional consequences for NK cell activity.