Expression of Activating KIR2DS2 and KIR2DS4 Genes after Hematopoietic Cell Transplantation: Relevance to Cytomegalovirus Infection

Abstract

The important role of activating Killer Immunoglobulin-like Receptors (aKIR) in protecting against cytomegalovirus (CMV) reactivation has been described previously in hematopoietic cell transplantation (HCT). More specifically, the presence of multiple aKIR and the presence of at least KIR2DS2 and KIR2DS4 in the donor genotype identified a group of HCT patients that were at low risk for CMV reactivation. However, CMV infection still occurs in patients with KIR protective genotype and the question was raised as to whether this was due to the lack of KIR expression. In this report, the expression of KIR2DS2 and 2DS4 gene, as measured by mRNA-based Q-PCR both in the donor cells and in the HCT recipient cells was studied relative to CMV reactivation. In the control samples from healthy HCT donors, the median range of for KIR2DS2 and KIR2DS4 expression was low with 35% considered null-expressers. Interestingly, KIR2DS2 and KIR2DS4 expression was elevated after HCT when compared to donor expression prior to transplant, and significantly elevated in the CMV viremic (V) compared to non-viremic (NV) HCT recipients. CMV seropositivity of donors was not associated with aKIR expression, and donor null-expression in those with KIR2DS2 or KIR2DS4 genotype did not predict for CMV reactivation in the recipient. After controlling for other transplant factors that included donor type (sibling or unrelated), transplant source -bone marrow (BM) or peripheral blood stem cells (PB) and acute GVHD grade, the result of the regression analysis of elevated KIR gene expression was found to be associated for both KIR2DS2 and KIR2DS4, with seven fold increase in risk for CMV reactivation. We speculate that the elevated aKIR expression in CMV viremic HCT recipients is either coincidental with factors that activate CMV or is initiated by CMV or cellular processes responsive to such CMV infection reactivation.

NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs

“…46 A striking observation in our study was the NKG2C-independent expansion of NK cells expressing activating KIR in CMV-seropositive donors. Of the 8 observed expansions, 2 were KIR2DS4 1 , 3 were KIR3DS1 1 , and 3 were KIR2DS2…”

Human Cytomegalovirus Infection Enhances NK Cell Activity In Vitro

“…One study demonstrated an elevated expression of aKIR (ie, KIR2DS2 and KIR2DS4) after HSCT compared with donor expression before HSCT, above all in CMV viremic compared with CMV nonviremic HSCT recipients. 32 …”

Immune reconstitution after hematopoietic cell transplantation

“…Natural killer cells are also involved in the innate immune responses against antimicrobial threats and have also been demonstrated to have cell-to-cell interactions that lead to the development of adaptive immune responses [10]. It has been recently demonstrated that recipients of T cell depleted transplants have diminished natural killer cell function (capability of releasing cytolytic granules in in vitro), whereas recipients of T cell replete HCT have normal natural killer cell function [50]. Natural killer cells are also hypothesized to have a role in suppressing GVHD through depletion of remaining host antigen presenting cells (APCs) [84], as well as allo-reactive donor T cells [85],…”