The effect of mouse cytomegalovirus infection on natural killer cell development following hematopoietic stem cell transplant

Abstract

Abstract Hematopoietic stem cell transplant (HSCT) is a treatment for patients with hematological malignancies who are not eligible to receive intensive cytoreductive therapy. Cytomegalovirus (CMV) is an extremely prevalent infection and in immune-compromised patients, it is a significant cause of morbidity and mortality. Approximately two-thirds of seropositive patients experience CMV reactivation following HSCT. There have been reports that CMV reactivation causes increased activation of NK cells which actually benefits graft-versus-tumor effects. Our study objective is to delineate the kinetics of this effect and determine whether there are long-term functional differences in NK cells. We hypothesized that immune reconstitution is impacted by CMV infection and that the lymphopenic and inflammatory environment post-HSCT detrimentally affects the immune response to CMV infection. Using a syngeneic HSCT model in C57BL/6 mice, we studied de novo NK cell repopulation. At day 8 post-transplant, mice were inoculated with a low dose of mouse CMV. We found a significantly higher viral burden in the HSCT recipients compared to control mice. We found that CMV-specific NK cells (Ly49H+) rapidly expanded following CMV infection post-HSCT, but experienced a population collapse after two weeks. This is possibly due to exposure to a primary virus infection early on in development and/or the increased viral burden. There was a higher frequency of mature NK cells and IFN-gamma producing NK cells following CMV infection in the HSCT environment, suggestive of increased activation and accelerated differentiation. The disproportionate loss of the Ly49H+ NK cells may cause long-term functional defects in the HSCT recipient immune response.