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¹ Department of Microbiology and Immunology, ² UNC Lineberger Comprehensive Cancer Center, ³ Department of Medicineand Pharmacology, ⁴ UNC School of Medicine Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599
⁵ Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15213

CORRESPONDENCE Roland Tisch: rmtisch{at}med.unc.edu

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, β cell–specific CD4⁺ T cells adoptively transferred into NOD.MerTK^KD/KD mice in which β 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⁺CD8⁺ 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.

P. Sen's present address is Division of Cell Biology and Immunology, Institute of Microbial Technology, Sector-39A, Chandigarh, 160036, India.

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