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MerTK is required for apoptotic cell–induced T cell tolerance
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2008
- Publisher :
- Rockefeller University Press, 2008.
-
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.
- Subjects :
- CD8 Antigens
T-Lymphocytes
T cell
Immunology
Apoptosis
Mice, Transgenic
Cell Separation
Biology
C-Mer Tyrosine Kinase
Models, Biological
Article
Diabetes Mellitus, Experimental
Immune tolerance
Mice
03 medical and health sciences
0302 clinical medicine
Mice, Inbred NOD
Proto-Oncogene Proteins
Immune Tolerance
medicine
Animals
Immunology and Allergy
Transgenes
030304 developmental biology
NOD mice
Wound Healing
0303 health sciences
c-Mer Tyrosine Kinase
GAS6
Receptor Protein-Tyrosine Kinases
Articles
Dendritic Cells
MERTK
Flow Cytometry
Interleukin-12
CD11c Antigen
MERTK Gene
medicine.anatomical_structure
Interleukin 12
Cancer research
030215 immunology
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 205
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....ad262b536f2199d58fee22c1f3ef5eba
- Full Text :
- https://doi.org/10.1084/jem.20062293