CXCR6(+) and NKG2C(+) Natural Killer Cells Are Distinct With Unique Phenotypic and Functional Attributes Following Bone Marrow Transplantation

Reactivation of human cytomegalovirus (HCMV) is a life-threatening complication in transplant patients. Natural Killer (NK) cells are the first lymphocyte lineage to reconstitute following an allogeneic hematopoietic stem cell transplant (HSCT). Amongst them, NK cell Group 2 isoform C/Killer cell lectin-like receptor subfamily C, member 2 (NKG2C)-expressing NK cells contribute significantly to patient protection upon HCMV reactivation. NKG2C(+) NK cells are capable of immunological memory, albeit NK cell memory is not restricted to them. Hepatic C-X-C Motif Chemokine Receptor 6 (CXCR6)-expressing NK cells also mediate memory responses in mice and humans. Small numbers of them circulate and can thus be studied in peripheral blood samples. We hypothesize that NKG2C(+) and CXCR6(+) NK cell subsets are distinct. To test our hypothesis, we used multi-parametric flow cytometry to determine the phenotypes and effector functions of CD56(bright) vs. CD56(dim) and NKG2C(+) vs. CXCR6(+) human NK cell subsets in the peripheral blood (PB) of pediatric transplant recipients monthly while monitoring patients for HCMV reactivation. Interestingly, we did not find any NKG2C(+)CXCR6(+) NK cells in the transplant recipients' peripheral blood, suggesting that NKG2C(+) and CXCR6(+) NK cells are distinct. Also, NKG2C-CXCR6- NK cells, rather than NKG2C(+) NK cells, made up most NK cells post-transplant, even in transplant recipients with HCMV viremia. In contrast to NKG2C(+) NK cells, CXCR6(+) NK cells appeared phenotypically less differentiated but were highly proliferative and produced IFN-gamma and TNF alpha. Our findings contribute to our understanding of post-transplant NK cell development and its implications for human health.