NK cells promote transplant tolerance by killing donor antigen-presenting cells

Abstract

Natural killer (NK) cells are programmed to kill target cells without prior antigen priming. Because of their potent cytolytic activities, NK cells are one of the key cell types involved in dismantling allografts. However, in certain transplant models, NK cells also express potent immunoregulatory properties that promote tolerance induction. The precise mechanism for such striking dichotomy remains unknown. In the present study, we showed in a skin transplant model that the skin allografts contain a subset of antigen-presenting cells (APCs) that can home to the recipient mice. We also showed that such graft-derived APCs are usually destroyed by the host NK cells. But in the absence of NK cells, donor APCs can survive and then migrate to the host lymphoid and extralymphoid sites where they directly stimulate the activation of alloreactive T cells. T cells activated in the absence of NK cells are more resistant to costimulatory blockade treatment, and under such conditions stable skin allograft survival is difficult to achieve. Our study identified a novel role for NK cells in regulating T cell priming in transplant models, and may have important clinical implications in tolerance induction.

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation

“…These authors found that deficiency in NK cells increased T cell proliferation and accelerated allograft rejection, whereas in NK cell sufficient mice, NK cells induced their immunomodulatory function by killing donor-derived dendritic cells that migrated to secondary lymphoid organs, leading to enhanced allograft survival. 19 These findings are coincident with those reported by Laffont et al, who also provided evidence for the role of NK cells recruited to the draining lymph nodes in the inhibition of the alloreactive T-cell activation through a perforin-mediated killing of donor-derived allogeneic dendritic cells. 20 …”

“…This effect would lead to attenuation of the direct pathway of antigen presentation as shown by others. 19,20,38 Yu et al, compared alloantigen-driven T cell homeostatic proliferation in lymphopenic environments of immunodeficient mice after allogeneic skin graft transplantation between Rag2 deficient (NK sufficient) and Rag2/gamma chain double-deficient (NK deficient) mice adoptively transferred with syngeneic T cells. These authors found that deficiency in NK cells increased T cell proliferation and accelerated allograft rejection, whereas in NK cell sufficient mice, NK cells induced their immunomodulatory function by killing donor-derived dendritic cells that migrated to secondary lymphoid organs, leading to enhanced allograft survival.…”

“…18 NK cells may also contribute to prolong graft survival and transplant tolerance by eliminating donor-derived antigen-presenting cells (APC) and limiting the direct pathway of antigen presentation and T cell priming in draining lymph nodes. 19,20 …”

The Innate Immune System in Allograft Rejection and Tolerance

“…In addition to their role promoting solid organ rejection, NK cells also facilitate tolerance induction (81)(82)(83). In a series of well-controlled experiments, Beilke et al (81) show that tolerance induction to fully mismatched islet allografts by either costimulatory blockade with CD154 Ab or Ab blockade of CD11a required the presence of both MHC class I expression and NK cells.…”

Fundamental Immunology of Skin Transplantation and Key Strategies for Tolerance Induction

“…Kroemer et al (2008b) reported that NK cells could reject skin allografts when stimulated with interleukin (IL)-15 in the absence of adaptive immune cells. However, recent studies have demonstrated that NK cells can kill allogeneic graft-derived APCs and prolong the survival of skin grafts through the inhibition of direct T cell priming or the elimination of activated alloreactive T cells in a perforin-dependent mechanism (Beilke et al 2005;Yu et al 2006). Thus, it is possible that NK cells have bidirectional effects on skin graft rejection and tolerance.…”