Formation of FcRγ-deficient NK cell subset associated with HCMV-reactivation in hematopoietic cell transplant recipients.

Abstract

131 Background: We have previously identified a novel subset of human NK cells that lacks FcRγ, a transmembrane signaling adaptor associated with CD16, the Fc receptor for IgG. These FcRγ-deficient NK cells (termed g-NK cells) display enhanced functional activity against target cells, including virus-infected cells, in concert with target-specific antibody molecules. The presence of g-NK cells in humans is associated with prior infection by human cytomegalovirus (HCMV). Additionally, g-NK cells are activated and expand robustly against HCMV-infected cells in the presence of HCMV-specific antibodies, consistent with predicted features of memory-like or adaptive NK cells. Recent studies have reported that expansion of a specific subset of NK cells with an adaptive phenotype can occur in response to HCMV reactivation after hematopoietic cell transplantation. Remarkably, patients with the expanded subset of NK cells showed reduced incidence of leukemia relapse and improved disease-free survival. Methods: Using blood samples obtained from BMT patients pre- and post-transplant, we have performed FACS-based phenotyping and ELISA-based serotyping analyses to explore whether HCMV-reactivation correlates with the generation of FcRγ-deficient NK cells in a bone marrow transplantation (BMT) setting. Results: Our data demonstrate that FcRγ-deficient NK cells appear in transplant patients following HCMV-reactivation, but not in the BMT patients without HCMV-reactivation. Phenotypic analysis indicates that these FcRγ-deficient NK cells display characteristics consistent with those observed in g-NK cells obtained from healthy HCMV-seropositive individuals, e.g. decreased expression of tyrosine kinase SYK. Conclusions: These results provide evidence in support of a causal relationship between HCMV infection and the generation of g-NK cells. Given the enhanced functional capability of g-NK cells against HCMV-infected target cells, the formation and functional activity of g-NK cells within BMT patients may contribute to the control of HCMV infection during the transplant procedure, and impact recovery from other diseases.