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The CD28-B7 family of receptor-ligand pairs regulates lymphocyte responses through costimulation and coinhibition. It includes checkpoint inhibitors, such as PD-1, which limit antitumor and antivirus T-cell responses. CD28 homolog (CD28H) and B7H7 have been identified as a receptor-ligand pair in this family, which has costimulatory activity in T cells. Here, we show that CD28H is expressed in primary natural killer (NK) cells and that it is a strong activator of NK cells through selective synergy with receptors NKp46 and 2B4 to induce degranulation, lysis of target cells, and production of proinflammatory cytokines. Expression of B7H7 on target cells enhanced both natural and antibody-dependent cellular cytotoxicity of NK cells. Mutation of tyrosine 192 on the CD28H cytoplasmic tail abolished NK-cell activation through CD28H. As B7H7 is broadly expressed in tumor tissues, we engineered a CD28H chimeric antigen receptor (CD28H-CAR) consisting of full-length CD28H fused to the cytoplasmic domain of T-cell receptor ζ chain. Remarkably, expression of CD28H-CAR in NK cells triggered lysis of B7H7 + HLA-E + tumor cells by overriding inhibition by the HLA-E receptor NKG2A. The cytoplasmic domains of CD28H and of the ζ chain were both required for this activity. Thus, CD28H is a powerful activation receptor of NK cells that broadens their antitumor activity and holds promise as a component of NK-based CARs for cancer immunotherapy.

CD28 Homolog Is a Strong Activator of Natural Killer Cells for Lysis of B7H7+ Tumor Cells