Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Lei Zhang, Matthew DeBerge, Jiaojin Wang, Anil Dangi, Xiaomin Zhang, Samantha Schroth, Zheng Zhang, Edward B. Thorp*, Xunrong Luo

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 + CD25 + Foxp3 + regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

Original languageEnglish (US)
Pages (from-to)674-685
Number of pages12
JournalAmerican Journal of Transplantation
Volume19
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • basic (laboratory) research/science
  • cell death: apoptosis
  • cytokines/cytokine receptors
  • immune regulation
  • immunobiology
  • immunosuppression/immune modulation
  • macrophage/monocyte biology: activation
  • organ transplantation in general
  • tolerance: mechanisms
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance'. Together they form a unique fingerprint.

  • Cite this