NK Cells: Not Just Followers But Also Initiators of Chronic Vascular Rejection

Abstract

Chronic graft rejection represents a significant threat to long-term graft survival. Early diagnosis, understanding of the immunological mechanisms and appropriate therapeutic management are essential to improve graft survival and quality of life for transplant patients. Knowing which immune cells are responsible for chronic vascular rejection would allow us to provide effective and appropriate treatment for these patients. It is now widely accepted that natural killer (NK) cells play an important role in chronic vascular rejection. They can either initiate chronic vascular rejection by recognizing missing self on the graft or be recruited by donor-specific antibodies to destroy the graft during antibody-mediated rejection. Whatever the mechanisms of activation of NK cells, they need to be primed to become fully activated and damaging to the graft. A better understanding of the signaling pathways involved in NK cell priming and activation would pave the way for the development of new therapeutic strategies to cure chronic vascular rejection. This review examines the critical role of NK cells in the complex context of chronic vascular rejection.

Keywords: antibody dependent cellular cytotoxicity; antibody mediated rejection; chronic rejection; missing self; natural killer cells.

FIGURE 1

Main inhibitory and activating receptors on NK cell surface. Default of inhibitory signals or excess of activating signals can lead to NK cell activation. KIRs, Killer Immunoglobin-like Receptors; NCRs, Natural Cytotoxicity Receptors; HLA, Human Leucocyte Antigen; MIC-A/B, MHC class I-related chain A/B; ULBPs, UL16-binding proteins.

FIGURE 2

NK cell education and activation during chronic vascular rejection. Schematic representation of the education process of NK cells during their maturation. The interaction between specific inhibitory KIRs on NK cell surface and HLA I on healthy cells allows NK cell to become responsive. Schematic representation of the three situations that can conduct to recipient NK cell activation during chronic vascular rejection. ADCC, Antibody Dependent Cell Cytotoxicity; DSA, Donor Specific Antibody; HLA-I, Human Leucocyte Antigen class I.

FIGURE 3

NK cell priming and activation pathways. The pathways involved in NK cell priming and activation as well as the drugs susceptible to block these pathways are depicted. IL15Rα, IL-15 receptor alpha subunit; IL15R, IL-15 receptor; DSA, Donor specific antibody; iKIR, inhibitory killer cell immunoglobulin-like receptors; MAPK, mitogen-activated protein kinase; HLA-I, Human Leucocyte Antigen class I; NFAT, nuclear factor of activated T-cells.