Anti-HLA-E Monoclonal antibody, clone 4E23IMB-F [APC]

The equilibrium of signaling through activating and inhibitory receptors dictates whether a given NK cell will execute cellular cytotoxicity. In this issue of the JCI, Kamiya et al. describe a novel approach to efficiently inhibiting surface expression of the inhibitory receptor CD94/NK group 2 member A (NKG2A) through retention of the protein in the endoplasmic reticulum. In adoptive transfer experiments into tumor-bearing immunodeficient mice, NKG2A(null) NK cells were significantly more effective at eliminating HLA-E-expressing tumor cells than NKG2A(+) NK cells. This study provides proof of concept for a new immunotherapeutic approach using NKG2A(null) NK cells.

Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.