MerTK is required for apoptotic cell-induced T cell tolerance.

Wallet, Mark A and Sen, Pradip and Flores, Rafael R and Wang, Yaming and Yi, Zuoan and Huang, Yingsu and Mathews, Clayton E and Earp, H Shelton and Matsushima, Glenn and Wang, Bo and Tisch, Roland (2008) MerTK is required for apoptotic cell-induced T cell tolerance. The Journal of experimental medicine, 205 (1). pp. 219-32. ISSN 1540-9538

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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.

Item Type: Article
Additional Information: Copyright of this article belongs to Rockefeller University Press.
Subjects: R Medicine > R Medicine (General)
Depositing User: Dr. K.P.S.Sengar
Date Deposited: 21 Feb 2012 18:06
Last Modified: 21 Feb 2012 18:06

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