Allelic Polymorphisms of Inhibitory Killer Immunoglobulin–Like Receptor Natural Killer Cell Function Can Also Influence the Graft-Versus-Leukemia Response

Abstract

Allogeneic hematopoietic stem-cell transplantations (HSCT) are recognized as a potentially curative treatment of choice for patients with acute leukemia and certain types of lymphoma who fail to sustain an initial complete remission, and are a favored option for patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in first remission who are at high risk of relapse. Although allogeneic HSCTs entail significant risks, they also confer on the transplantation recipient an enhanced resistance to disease recurrence that is not observed after autologous or syngeneic HSCT. The basis for this graft-versus-leukemia effect is complex and still poorly understood. However, both innate and adaptive immune responses that are directed against leukemia cells have been implicated, particularly the contributions of donor-derived natural killer (NK) cells and those of T cells that are specific for either alloantigens that are broadly expressed or differentially expressed by hematopoietic cells of the host, or oncofetal and disease-specific antigens that are aberrantly expressed by leukemia cells. NK cells can be activated through a broad array of activating receptors, such as NKG2D, the natural cytotoxicity receptors NKp30, NKp44, NKp46, and NKp80, and activating receptors of the killer immunoglobulin–like receptor (KIR) complex. These receptors endow NK cells with the capacity to distinguish and respond to autologous cells that differentially express their respective ligands in response to viral infection, malignant transformation, or other types of stress. The KIRs are encoded by a complex of genes on chromosome 19. The KIRs inherited on each haplotype differ in content and function and include KIRs that inhibit or activate the NK cell on binding to their cognate ligands. The ligands for inhibitory KIRs are HLA class I alleles. KIR2DL3 binds HLA-C alleles that contain asparagine at position 80 (C1 alleles), whereas KIR2DL1 binds HLA-C alleles bearing lysine at that position (C2 alleles). KIR3DL1 binds HLA-BW4, whereas KIR3DL2 binds HLA-A3 and -A11 alleles. The activating KIR2DS4 is also known to bind HLA alleles (HLA-A3, -A11, or certain HLA-C alleles). KIR2DS1, like 2DL1, can also bind to HLA-C2 alleles. However, if the 2DS1 donor is also homozygous for an HLA-C2 allele (C2/C2), the NK cells are rendered hyporesponsive or tolerant. The ligands for the other activating KIRs that induce NK cytotoxic activity are unknown. The KIR genes exhibit significant diversity at two levels: allelic polymorphisms within the KIR genes themselves, and differences in the number and type of activating and inhibitory KIR genes inherited on a given haplotype. Analysis of the KIR gene complex has led to the recognition of a series of KIR gene haplotypes that can be divided into two major groups, each containing distinctive sets of KIR genes in their centromeric and telomeric regions. Group A KIR haplotypes differentially contain genes for four inhibitory receptors, KIR2DL3 and KIR2DL1 in the centromeric region and KIR3DL1 and KIR3DL2 in the telomeric region, but only one activating receptor, KIR2DS4. In contrast, KIR B haplotypes contain the inhibitory receptor KIR2DL2 and the activating receptor 2DS2 in the centromeric region and variably contain three activating receptors, 2DS1, 2DS3, and 2DS5, and one inhibitory receptor, 2DL5, in the telomeric region (Fig 1). Because NK cells can be activated through many receptors that encounter their ligands on stressed cells, control of NK cell activity is both essential and necessarily nuanced. Active NK cell tolerance is provided by inhibitory KIR receptors that continuously encounter their cognate class I HLA ligand on normal cells in their environment. These so-called licensed NK cells are differentially armed to distinguish cells that do or do not express their cognate HLA ligand. Detection and binding of this self-ligand on a potential target by inhibitory KIRs induces an inhibitory response. However, if the NK cell’s inhibitory KIR does not encounter its HLA ligand, and expression of ligands for activating KIRs is sufficient, the NK cell’s cytolytic complex is activated and the target is lysed. Additional mechanisms are also operative in the control of NKcell–mediated autoreactivity. Because inheritance of HLA haplotypes on chromosome 6 and KIR haplotypes on chromosome 19 are independent, most individuals inherit inhibitory KIRs for which the cognate class I ligand is not present in the host’s HLA genotype. Unlike T cells, NK cells that express KIRs that develop in the absence of cognate HLA ligands are not deleted. Rather, these so-called unlicensed NK cells continue to be generated but are functionally hyporesponsive JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 30 OCTOBER 2