NK cells: elusive participants in transplantation immunity and tolerance

Abstract

NK cells constitute an innate MHC class I-reactive lymphoid population that rapidly responds to infection, injury, or cell distress. In the transplant field, NK cells have most often been associated with pro-inflammatory immunity resulting in the exacerbation of allograft injury. Despite this general view of NK cell reactivity, it has been challenging to assign unambiguous obligate roles for NK cells in the allograft response. While recent reports continue to provide evidence supporting a role for NK cells in promoting both acute and chronic rejection, there are also a growing number of studies that illustrate an alternative role for NK cells in promoting allograft survival and tolerance. This review addresses the plasticity of NK responses in transplantation by suggesting specific 'checkpoints' whereby NK cells can either enhance or inhibit the allograft response in vivo.

Figure 1

Major proposed checkpoints in NK cell-mediated impact on allograft immunity. As described in the text, we propose three key areas, or ‘checkpoints’ whereby NK cells positively or negatively impact T cell-dependent allograft immunity. (1) Checkpoint 1: NK cells can directly lyse donor DC resulting in blunted direct antigen (donor APC-dependent) presentation to host T cells and enhanced release of donor antigens acquired by host APC (indirect, or host-APC dependent presentation). (2) Checkpoint 2: NK cells can either augment or inhibit the capacity of host APC to direct donor-derived antigens to reactive T cell. (3) Checkpoint 3: NK cells can enhance or inhibit T cell reactivity through a direct interaction with activated T cells. (4) Checkpoint 4: NK cells and regulatory T cells (Treg) tend to cross-regulate one another to either promote or inhibit regulatory activity.