The Journal of Experimental Medicine
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Published online January 14, 2008
doi:10.1084/jem.20062293
The Journal of Experimental Medicine, Vol. 205, No. 1, 219-232
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Wallet et al.
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ARTICLE

 MerTK is required for apoptotic cell–induced T cell tolerance

Mark A. Wallet1, Pradip Sen1, Rafael R. Flores1, Yaming Wang1, Zuoan Yi1, Yingsu Huang1, Clayton E. Mathews5, H. Shelton Earp2,3, Glenn Matsushima1,2,4, Bo Wang1, and Roland Tisch1,2

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.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/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{alpha}+ 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.

Abbreviations used: AC, apoptotic cell; BMDC, BM-derived DC; DT, diphtheria toxin; DTR, DT receptor; Gas6, growth arrest–specific protein-6; MerTK, Mer tyrosine kinase; NOD, nonobese diabetic; PLN, pancreatic lymph node; PS, phosphatidylserine; RTK, receptor tyrosine kinase; RPE, retinal pigment epithelial cell; sDC, splenic DC; STZ, streptozotocin.

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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