TY  - JOUR
N1  - Copyright of this article belongs to Rockefeller University Press.
ID  - open1078
UR  - http://jem.rupress.org/content/205/1/219.long
IS  - 1
A1  - Wallet, Mark A
A1  - Sen, Pradip
A1  - Flores, Rafael R
A1  - Wang, Yaming
A1  - Yi, Zuoan
A1  - Huang, Yingsu
A1  - Mathews, Clayton E
A1  - Earp, H Shelton
A1  - Matsushima, Glenn
A1  - Wang, Bo
A1  - Tisch, Roland
Y1  - 2008/01/21/
N2  - 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.
PB  - Rockefeller University Press
JF  - The Journal of experimental medicine
VL  - 205
SN  - 1540-9538
TI  - MerTK is required for apoptotic cell-induced T cell tolerance.
SP  - 219
AV  - restricted
EP  - 32
ER  -