Activating KIR: iN Kase of KIR-ligand mismatch

In this issue of Blood, Mancusi et al demonstrate that haploidentical hematopoietic stem cell transplantation (HSCT) from killer immunoglobulin-like receptor (KIR) ligand–mismatched donors with concomitant activating KIRs reduces nonrelapse mortality (NRM).¹ 

The role of inhibitory KIRs (iKIRs) in natural killer (NK) cell alloreactivity has been extensively described and clinically substantiated, if not rigorously proven.²  Briefly, iKIRs are thought to interact with and be educated by self–major histocompatibility complex (MHC) class I ligands.³  The subsequent absence of these ligands, as in the case of MHC-class I mismatch, is thought to disinhibit the NK cell and allow for activation and eventual cytotoxicity. Indeed, in this particular report, the patients with acute myelogenous leukemia who received grafts from NK-alloreactive donors fared better in terms of event-free survival (EFS).

What has been less understood is the role of activating KIRs (aKIRs) on NK cells, both in terms of disease control and immune function. The aKIR molecules are structural homologs of their inhibitory counterparts, but they signal through intracellular adaptor proteins.⁴  Although the ligands for many iKIRs have been identified, only the interaction between activating KIR2DS1 and HLA-C2 has been well established and accepted. To further complicate this, it is also unknown how the inhibitory and aKIR molecules interact with each other in the process of NK cell education.

The bulk of the HSCT literature related to aKIRs has focused on its effects on disease control. Several reports have documented the contribution of aKIRs in some respect to improvements in disease outcomes, particularly in leukemia.^5,6  Of these, at least one has also demonstrated an impact of aKIRs on NRM⁷ ; interestingly, this was also found in the haploidentical setting.

In contrast, Mancusi et al describe a beneficial effect of aKIRs on EFS and NRM but not on leukemia relapse. Furthermore, this effect is seen only in patients with NK-alloreactive donors. Multivariate analysis demonstrates a particular role for KIR2DS1 and KIR3DS1 in this process, consistent with the observation that Tel B/X donor KIR genotypes are also associated with improved EFS and NRM.

This benefit in NRM is presumed to be the result of fewer infectious complications, particularly in the first months after transplantation. The authors attempt to validate this hypothesis by demonstrating that the presence of aKIRs does not affect healthy NK cell alloreactivity against leukemia but does affect the in vitro response to pathogens. These findings suggest that the antitumor impact of NK cell alloreactivity is not dependent on aKIRs but rather that a disinhibition of NK cells subsequently allows for aKIRs to exert cytotoxic effects. Whether this sequence is congruous to the natural development of NK cells in healthy individuals is not known.

Importantly, the in vitro validations are done only with HLA-C1 donor NK cells against HLA-C2 targets. Although the results corroborate the clinical findings, the question remains of whether this applies to C2 donors when faced with C1 targets. Previous reports suggest that the activation potential of 2DS1 is curbed when those NK cells are also HLA-C2–positive.⁸  In addition, although this phenomenon appears to be somewhat dependent on HLA-C2, it is not completely known whether, in the setting of true infection, there are other ligands for aKIRs that are non-HLA class I–associated.

This manuscript is among the first to use both clinical and in vitro data to suggest a beneficial effect of aKIRs on immune function. However, there are conflicting data about the role of aKIRs in fighting infection. Some studies suggest that KIR3DS1 is beneficial in the setting of HIV infection, but only for HLA-Bw4 patients.⁹  Other studies suggest a detrimental effect of KIR2DS3 in hepatitis C infection, associated in this instance with HLA-C2 positivity.¹⁰  The present study attempts to dissect this effect of aKIRs; however, no conclusions can be made about viral immunity, one of the major issues in HSCT.

Although the findings in this elegant study appear to be straightforward, our immature (but evolving) knowledge on NK cell education, function of aKIRs, and the interaction between iKIRs and aKIRs cloud our ability to rigorously apply this algorithm to our patients. With the recent advances in genotyping and flow cytometry staining protocols, the true function and potential of aKIRs may be better elucidated. This, in conjunction with clinical data such as those presented here, may eventually grant us another selection tool for NK cells in our unceasing quest to optimize allogeneic HSCT.