Two signals that trigger NK cell aggression against tumors

When it comes to the generation of immune responses, 2 signals are better than 1. For a long time, we have known that during T-cell activation, the T-cell receptor provides signal 1, and costimulation by CD28 provides signal 2. In this issue of Blood, Gao and colleagues (page 4456) now demonstrate that 2 signals are also required for effective natural killer (NK) cell responses against tumors. NK cells express multiple activating receptors with diverse structures and specificities. One of these receptors, Ly-49D, recognizes a major histocompatibility complex (MHC) class I molecule called H-2Dd. Recognition of H-2Dd by Ly-49D triggers NK cell-mediated cytotoxicity and cytokine secretion in vitro. NK cells also express several costimulatory molecules, including CD28, which interacts with B7-1/2 on target cells. In the present study, Gao and colleagues challenged mice with several variants of 2 tumor cell lines expressing either H-2Dd or B7-1, both molecules, or neither. Strikingly, mice efficiently rejected tumors expressing both H-2Dd and B7-1 using NK cell-mediated responses. In contrast, responses against tumors expressing neither or only one of the Ly49D/CD28 ligands were inefficient.

Although expression of B7-1/2 on target cells has been shown to augment NK cell-mediated cytotoxicity, signal 2 appears to more than merely enhance NK cell effector capacities in this study. Rejection of tumors expressing H-2Dd and B7-1 paralleled increased proliferation of NK cells, primarily those expressing Ly-49D. Increased proliferation did not immediately result in increased NK cell numbers, due to significant apoptosis of activated cells. However, 3 weeks after the contraction phase, NK cell numbers remained relatively high. Therefore, coengagement of Ly-49D and CD28 seems to be critical for expansion of an NK cell short-term memory compartment. This expansion of “specific” NK cells may drive the growth and activation of bystander NK cells, which may further contribute to tumor rejection.

As well as adding a new layer of complexity to the biology of NK cells, this study renews enthusiasm for NK cell-mediated immunotherapy of tumors, leukemias, and other hematologic malignancies in particular. One could predict that in haplotype-mismatch hematopoietic transplantation, in which the donor and recipient are mismatched for the HLA class I loci, donor NK cells may recognize recipient MHC class I molecules via activating receptors. In the presence of costimulation, these alloreactive NK cells may expand significantly and lyse host lymphohematopoietic cells, including leukemia cells. Moreover, given the multiplicity of activating and costimulatory molecules expressed on NK cells, many other tumors should elicit signal 1 and signal 2. Thus, provoking NK cells with 2 signals may have broad therapeutic potential and, indeed, be better than 1.