Functional Reconstitution of Natural Killer Cells in Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are important in mediating immunity against both leukemia and pathogens. Although NK cell numbers generally reconstitute within a month, the acquisition of mature NK cell phenotype and full functional competency can take 6 months or more, and is influenced by graft composition, concurrent pharmacologic immunosuppression, graft-versus-host disease, and other clinical factors. In addition, cytomegalovirus infection and reactivation have a dominant effect on NK cell memory imprinting following allogeneic HSCT just as it does in healthy individuals. Our understanding of NK cell education and licensing has evolved in the years since the "missing self" hypothesis for NK-mediated graft-versus-leukemia effect was first put forward. For example, we now know that NK cell "re-education" can occur, and that unlicensed NK cells can be more protective than licensed NK cells in certain settings, thus raising new questions about how best to harness graft-versus-leukemia effect. Here, we review current understanding of the functional reconstitution of NK cells and NK cell education following allogeneic HSCT, highlighting a conceptual framework for future research.

Keywords: NK cell; NK cell education; allogeneic HSCT; cytomegalovirus; memory NK cell.

Figure 1

NK cell reconstitution and education following allogeneic HSCT. Reconstituting NK cells can be derived from (i) NK cell precursors, ranging from hematopoietic stem cells through to common lymphoid progenitors, that differentiate into NK cells in the bone marrow, and (ii) transferred mature NK cells, which carry with them a mature NK phenotype and NK memory. NK cells are educated in the bone marrow but can be “re-educated” in the periphery. It is uncertain whether recipient cells (generally non-hematopoietic only post transplant) are involved in NK cell education. In HLA-mismatched transplants, NK cells that are licensed by inhibitory KIRs that recognize a ligand (HLA) that is expressed only by the donor and not the recipient may lyse recipient cells (“missing self”) and contribute to the GVL effect. Conversely, an NK cell that has not encountered a cognate MHC class I for its inhibitory KIR(s) is “unlicensed” and hyporesponsive, but can acquire functional competency when stimulated by pro-inflammatory cytokines, for example, in the setting of CMV reactivation.