The biology of NK cells and their receptors affects clinical outcomes after hematopoietic cell transplantation (HCT)

Abstract

Natural killer (NK) cells were first identified for their capacity to reject bone marrow allografts in lethally irradiated mice without prior sensitization. Subsequently, human NK cells were detected and defined by their non-major histocompatibility complex (MHC)-restricted cytotoxicity toward transformed or virally infected target cells. Karre et al. later proposed 'the missing self hypothesis' to explain the mechanism by which self-tolerant cells could kill targets that had lost self MHC class I. Subsequently, the receptors that recognize MHC class I to mediate tolerance in the host were identified on NK cells. These class I-recognizing receptors contribute to the acquisition of function by a dynamic process known as NK cell education or licensing. In the past, NK cells were assumed to be short lived, but more recently NK cells have been shown to mediate immunologic memory to secondary exposures to cytomegalovirus infection. Because of their ability to lyse tumors with aberrant MHC class I expression and to produce cytokines and chemokines upon activation, NK cells may be primed by many stimuli, including viruses and inflammation, to contribute to a graft-versus-tumor effect. In addition, interactions with other immune cells support the therapeutic potential of NK cells to eradicate tumor and to enhance outcomes after hematopoietic cell transplantation.

Keywords: NK cells; cytomegalovirus; innate immunity; killer immunoglobulin-like receptors; leukemia; transplantation.

Fig. 1. Role of KIR ligand mismatch in GVL

This figure illustrates the role of reconstituting NK cells after transplantation. (A) In the setting of KIR-ligand (e.g. HLA/MHC) match, reconstituting NK cells can be educated by class I MHC presentation by donor hematopoietic cells, recipient non-hematopoietic cells or both. This leads to a gain of function. In the absence of KIR ligand mismatch or a missing self setting, donor NK cells would be tolerant against recipient residual leukemia despite expression of activating ligands. Normal recipient tissue is also tolerant based on both inhibition by MHC class I and lack of activating ligands. (B) In contrast, a KIR ligand mismatch in the graft versus host direction results in missing self combined with NK cell activation of stress ligands (e.g. MICA/B) leads to recipient leukemia killing and protection from relapse. Normal tissue is still tolerant based on absence of activating ligands despite absence of inhibition through class I MHC receptors. If educating cells are missing or contain mismatched ligands for inhibitory receptors, donor NK cells will be hypo-responsive and will not be capable of killing leukemic targets, even if inhibitory signaling is disrupted and activating signals are triggered.

Fig. 2. The KIR gene cluster is comprised of activating and inhibitory KIR genes on the centromeric or telomeric sides of chromosome 19

This upper figure depicts the KIR locus on chromosome 19. The individual genes circled depict those defined as KIR B on the centromeric (Cen) or telomeric (Tel) side of the chromosome. The KIR A haplotype has absence of KIR B defining genes. The KIR B haplotype contains at least one of these KIR B motifs. The presence of 1 or 2 KIR B motifs on the Cen or Tel portion determines the B Content score and correlation with relapse protection leads to a KIR Donor Assignment designation (lower table).