MERTK as negative regulator of human T cell activation

J Leukoc Biol. 2015 Apr;97(4):751-60. doi: 10.1189/jlb.3A0714-334R. Epub 2015 Jan 26.


The aim of this study was to test the hypothesis whether MERTK, which is up-regulated in human DCs treated with immunosuppressive agents, is directly involved in modulating T cell activation. MERTK is a member of the TAM family and contributes to regulating innate immune response to ACs by inhibiting DC activation in animal models. However, whether MERTK interacts directly with T cells has not been addressed. Here, we show that MERTK is highly expressed on dex-induced human tol-DCs and participates in their tolerogenic effect. Neutralization of MERTK in allogenic MLR, as well as autologous DC-T cell cultures, leads to increased T cell proliferation and IFN-γ production. Additionally, we identify a previously unrecognized noncell-autonomous regulatory function of MERTK expressed on DCs. Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK ligand PROS1. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine proproliferative mechanism. Collectively, these results suggest that MERTK on DCs controls T cell activation and expansion through the competition for PROS1 interaction with MERTK in the T cells. In conclusion, this report identified MERTK as a potent suppressor of T cell response.

Keywords: TAM receptors; suppression; tolerogenic dendritic cells.

Publication types

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

MeSH terms

  • Antigens, Bacterial / immunology
  • Autocrine Communication
  • Blood Proteins / physiology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / enzymology*
  • Cell Differentiation
  • Cell Division
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / drug effects
  • Dendritic Cells / enzymology*
  • Dendritic Cells / immunology
  • Dexamethasone / pharmacology
  • Enzyme Induction / drug effects
  • Humans
  • Immune Tolerance / physiology*
  • Immunologic Memory
  • Interferon-gamma Release Tests
  • Lymphocyte Activation / physiology*
  • Lymphocyte Culture Test, Mixed
  • Monocytes / cytology
  • Protein S
  • Proto-Oncogene Proteins / physiology*
  • Receptor Protein-Tyrosine Kinases / physiology*
  • T-Cell Antigen Receptor Specificity
  • Up-Regulation / drug effects
  • c-Mer Tyrosine Kinase


  • Antigens, Bacterial
  • Blood Proteins
  • PROS1 protein, human
  • Protein S
  • Proto-Oncogene Proteins
  • Dexamethasone
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase