One of the main mechanisms thought to be responsible for the induction of allograft tolerance is the generation of MHC-class-II-restricted CD4+regulatory T cells, but a study published in Nature Medicine has uncovered an unexpected role in tolerance induction for MHC-class-I-dependent responses that involve natural killer (NK) cells. This is in contrast to previous studies that show a role for NK cells in inflammation and graft injury.

The authors used a mouse model of tolerance to islet allografts induced by monoclonal antibody specific for CD40 ligand (CD40L). Surprisingly, they showed that, although antibody treatment was ineffective at prolonging graft survival in MHC-class-I-deficient mice, the requirement for MHC class I molecules did not depend on CD8+ T cells, because mice that were depleted of CD8+ T cells could accept islet allografts long-term in the presence of CD40L-specific monoclonal antibody. Therefore, the authors proposed that innate NK and NKT cells, which also require host expression of MHC class I molecules, might be involved in allograft tolerance.

Mice that were depleted of NK1.1+ cells before transplantation did not have prolonged graft survival in the presence of CD40L-specific antibody, which confirms a role in tolerance induction for NK and/or NKT cells, both of which express NK1.1 in the mouse strain that was used. CD1-deficient recipients, which do not have NKT cells but are NK-cell replete, had long-term survival of islet allografts with CD40L-specific antibody treatment, showing that NK cells are sufficient for MHC-class-I-dependent tolerance induction in this model.

Experiments using F1 (self × donor) allografts showed that the direct activation of NK cells by the absence of host MHC class I molecules on the graft (that is, by 'missing self') is not required for the tolerance that is induced by CD40L-specific antibody. Instead, NK cells modulate the host T-cell response to donor antigen-presenting cells (APCs) in the presence of CD40L-specific antibody, as shown when mice were immunized in the footpad with allogeneic APCs; mice that received CD40L-specific antibody had a marked reduction in the T-cell response in the draining lymph node, but this reduction was abrogated by NK-cell depletion. Using perforin-deficient mice reconstituted with perforin-competent NK cells, the authors showed that perforin production by NK cells is required for tolerance induction.

This result has implications for the design of tolerance-inducing protocols, which should promote the graft-protective role of NK cells while inhibiting the graft-destructive role.