MerTK is required for apoptotic cell-induced T cell tolerance.

Abstract

Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTK(KD/KD)) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTK(KD/KD) versus NOD mice expressing the transgenic BDC T cell receptor. In addition, beta cell-specific CD4(+) T cells adoptively transferred into NOD.MerTK(KD/KD) mice in which beta cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c(+)CD8alpha(+) DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.

• Authors: Mark A Wallet, Pradip Sen, Rafael R Flores, Yaming Wang, Zuoan Yi, Yingsu Huang, Clayton E Mathews, H Shelton Earp, Glenn Matsushima, Bo Wang, Roland Tisch
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 205 Issue 1 Pg. 219-32 (Jan 21 2008) ISSN: 1540-9538 [Electronic] United States
• PMID: 18195070 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD11c Antigen
• CD8 Antigens
• CD8 antigen, alpha chain
• Proto-Oncogene Proteins
• Interleukin-12
• Mertk protein, mouse
• Receptor Protein-Tyrosine Kinases
• c-Mer Tyrosine Kinase

Topics

• Animals
• Apoptosis
• CD11c Antigen (biosynthesis)
• CD8 Antigens (biosynthesis)
• Cell Separation
• Dendritic Cells
• Diabetes Mellitus, Experimental
• Flow Cytometry
• Immune Tolerance
• Interleukin-12 (metabolism)
• Mice
• Mice, Inbred NOD
• Mice, Transgenic
• Models, Biological
• Proto-Oncogene Proteins (genetics, physiology)
• Receptor Protein-Tyrosine Kinases (genetics, physiology)
• T-Lymphocytes (metabolism, pathology)
• Transgenes
• Wound Healing
• c-Mer Tyrosine Kinase