Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation

Abstract

Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value.

Pretransplant adaptive NKG2C+ NK cells protect against cytomegalovirus infection in kidney transplant recipients

“…NK cells with the risk of CMV infection might indirectly reflect the action of other immune cells. 55 The present data support a protective role played by NKG2C+ NK cells in the control of posttransplant CMV infection; yet, viremia was detected in some patients with high levels of NKG2C+ NK cells.…”

“…We addressed whether the association of adaptive NKG2C+ NK cells with the risk of CMV infection might indirectly reflect the action of other immune cells . Assessing the relation of adaptive NKG2C+ and CMV‐specific T cells in the same KTR cohort was not feasible due to the insufficient availability of cryopreserved samples.…”

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

“…An up-regulation of inhibiting and stimulating NKG2 receptors was observed after allogeneic or autologous haematopoietic stem cell transplantation and in patients with rheumatoid arthritis, whereby a gene polymorphism of NKG2 was found to be associated with susceptibility and severity of rheumatoid arthritis [13][14][15]. Certain CD158 determinants summarized as killer cell immunoglobulin-like receptors (KIR) were found to be associated with RM [16][17][18][19] as well as control of viral infection, chronic rejection and graft loss in renal transplantation [20,21].…”

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

“…NK cells can release EVs loaded with several cytotoxic proteins (85,86), including perforin and FasL, which can induce lysis of activated T lymphocyte and thus possibly blunt inflammation (65,87).…”