title: 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.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wallet
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Flores
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.forename: Zuoan
authors.initials: Z
authors.lastname: Yi
authors.forename: Yingsu
authors.initials: Y
authors.lastname: Huang
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Glenn
authors.initials: G
authors.lastname: Matsushima
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D017209:Apoptosis; D039521:CD11c Antigen / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002469:Cell Separation; D003713:Dendritic Cells; D003921:Diabetes Mellitus, Experimental; D005434:Flow Cytometry; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D019076:Transgenes; D014945:Wound Healing; D000076202:c-Mer Tyrosine Kinase
chemical_list: D039521:CD11c Antigen; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D011518:Proto-Oncogene Proteins; D018664:Interleukin-12; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase