MerTK regulates thymic selection of autoreactive T cells.
T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) are believed to be the result in part of inefficient negative selection of self-specific thymocytes. However, the events regulating thymic negative selection are not fully understood. In the current study, we demonstrate that nonobese diabetic (NOD) mice lacking expression of the Mer tyrosine kinase (MerTK) have reduced inflammation of the pancreatic islets and fail to develop diabetes. Furthermore, NOD mice deficient in MerTK expression (Mer(-/-)) exhibit a reduced frequency of beta cell-specific T cells independent of immunoregulatory effectors. The establishment of bone marrow chimeric mice demonstrated that the block in beta cell autoimmunity required hematopoietic-derived cells lacking MerTK expression. Notably, fetal thymic organ cultures and self-peptide administration showed increased thymic negative selection in Mer(-/-) mice. Finally, thymic dendritic cells (DC) prepared from Mer(-/-) mice exhibited an increased capacity to induce thymocyte apoptosis in a peptide-specific manner in vitro. These findings provide evidence for a unique mechanism involving MerTK-mediated regulation of thymocyte negative selection and thymic DC, and suggest a role for MerTK in contributing to beta cell autoimmunity.
Wallet
Mark A
MA
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599-7020, USA.
Flores
Rafael R
RR
Wang
Yaming
Y
Yi
Zuoan
Z
Kroger
Charles J
CJ
Mathews
Clayton E
CE
Earp
H Shelton
HS
Matsushima
Glenn
G
Wang
Bo
B
Tisch
Roland
R
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D007109:Immunity; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D012641:Selection, Genetic; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D000076202:c-Mer Tyrosine Kinase
D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase