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

Abstract

Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were implicated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting properties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic alloresponses refractory to current immunosuppression.

Innate immune cellular therapeutics in transplantation

“…In the setting of transplantation, NK cells have been found to participate in both rejection and tolerance, likely due to the distinct functions of their various subsets or differentiation states ( 248 ). Despite these mixed findings, several preclinical studies support a role for NK cells in inducing allograft tolerance ( 110 , 111 , 113 , 121 – 123 , 249 , 250 ). Firstly, NK cells were shown to attenuate the severity of GVHD in mice by suppressing activated alloreactive T cells, mediated by perforin and FasL signaling ( 249 ).…”

“…Additionally, NK cells were shown to delay skin graft rejection through cytotoxic killing of donor-derived APCs, which would otherwise activate host alloimmune T cells ( 110 , 111 ). NK cells also delayed rejection of murine skin grafts by suppressing alloimmune T cell responses directly, either through competition for shared growth factors or cytotoxic killing ( 113 , 250 ). Finally, upregulation of the NKG2A receptor in NK cells following islet transplantation stimulated secretion of IL-22, which attenuated inflammation and prolonged allograft survival ( 123 ).…”

The impact of CD160 deficiency on alloreactive CD8 T cell responses and allograft rejection

“…Abatacept (human recombinant CTLA-4.Ig, Bristol-Myers Squibb) or irrelevant human IgG1 control were administered i.p. at day 0 (1 mg), day 7 (0.5 mg), and day 14 (0.25 mg) to recipient B6 WT and CD160 KO mice that were grafted with allogeneic bm1 tail skin under deep anesthesia, following a general procedure previously reported [43].…”