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

Research output: Contribution to journalArticlepeer-review

Authors

  • J I Rodriguez-Barbosa
  • M C Ferreras
  • L Buhler
  • P Schneider
  • J A Perez-Simon
  • M L Del Rio-Gonzalez

Colleges, School and Institutes

External organisations

  • h Acción Estratégica en Salud , Consorcio CIBER-ONC.
  • b Department of Animal Health, Mountain Livestock Institute (CSIC), School of Veterinary Sciences , University of Leon , Leon , Spain.
  • c Visceral and Transplantation Surgery, Department of Surgery , University Hospitals of Geneva and Faculty of Medicine , Geneva , Switzerland.
  • d MRC Centre of Immune Regulation, School of Immunity and Infection, Medical School , University of Birmingham , United Kingdom.
  • e Department of Biochemistry , University of Lausanne , Epalinges , Switzerland.

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.

Details

Original languageEnglish
JournalMabs
Early online date23 Jul 2018
Publication statusE-pub ahead of print - 23 Jul 2018

Keywords

  • NK cells, CD8 T cells, bm1, MHC class I skin graft, transplantation, graft rejection