MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

J Exp Med. 2021 Oct 4;218(10):e20200464. doi: 10.1084/jem.20200464. Epub 2021 Aug 20.

Abstract

Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigens / immunology
  • Antigens / metabolism
  • Autoimmunity / physiology*
  • CD11 Antigens / metabolism
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Type 1 / enzymology
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Humans
  • Islets of Langerhans / enzymology*
  • Islets of Langerhans / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Neoplasms, Experimental / enzymology
  • Neoplasms, Experimental / immunology
  • Phagocytes / immunology
  • Phagocytes / physiology*
  • Piperazines / pharmacology
  • T-Lymphocytes / immunology*
  • c-Mer Tyrosine Kinase / genetics
  • c-Mer Tyrosine Kinase / immunology*
  • c-Mer Tyrosine Kinase / metabolism

Substances

  • Antigens
  • CD11 Antigens
  • Itgax protein, mouse
  • Piperazines
  • UNC2025
  • Mertk protein, mouse
  • c-Mer Tyrosine Kinase
  • Adenine