Transient Systemic Inflammation Does Not Alter the Induction of Tolerance to Gastric Autoantigens by Migratory Dendritic Cells
Transient Systemic Inflammation Does Not Alter the Induction of Tolerance to Gastric Autoantigens by Migratory Dendritic Cells
复制标题
DOI：
10.4049/jimmunol.1303429
复制
发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
van Driel, Ian R.
中科院分区：
文献类型：
--
作者：
Bourges, Dorothee;Ross, Ellen M.;van Driel, Ian R.
已经提出，在炎症过程中呈递自身抗原的树突状细胞（DC）的激活可能导致自身反应性T细胞的激活和自身免疫的发展。为了验证这一假设，我们研究了在自身免疫性胃炎中识别的自身抗原的呈递，胃H+/K+ ATP酶，其在胃中天然表达，并组成性地在胃引流淋巴结中呈递。全身给予小鼠TLR 9激动剂CpG DNA、激动剂抗CD 40 Ab或TLR 4激动剂LPS均未能消除H+/K+ ATP酶特异性CD 4 T细胞的外周克隆缺失过程或促进自身免疫性胃炎的发展。我们证明，从胃引流淋巴结迁移的DC是唯一的DC子集能够组成型提出内源性胃H+/K+ ATP酶自身抗原在其正常的生理环境。共刺激分子的分析表明，相对于居民DC，迁移性DC在稳态下显示部分活化的表型。此外，迁移性DC对短暂暴露于TLR激动剂的刺激是难治的，因为它们不能上调共刺激分子，分泌大量的炎性细胞因子，或诱导效应T细胞的分化。总之，这些数据表明，短暂的全身性炎症未能打破对胃自身抗原的耐受性，因为呈递胃自身抗原的迁移性DC在这种条件下保持致耐受性，证明了外周耐受性的稳健性质。
It has been proposed that activation of dendritic cells (DCs) presenting self-antigens during inflammation may lead to activation of autoreactive T cells and the development of autoimmunity. To test this hypothesis, we examined the presentation of the autoantigen recognized in autoimmune gastritis, gastric H+/K+ ATPase, which is naturally expressed in the stomach and is constitutively presented in the stomach-draining lymph nodes. Systemic administration to mice of the TLR9 agonist CpG DNA, agonist anti-CD40 Ab, or TLR4 agonist LPS all failed to abrogate the process of peripheral clonal deletion of H+/K+ ATPase-specific CD4 T cells or promote the development of autoimmune gastritis. We demonstrated that migratory DCs from the stomach-draining lymph nodes are the only DC subset capable of constitutively presenting the endogenous gastric H+/K+ ATPase autoantigen in its normal physiological context. Analysis of costimulatory molecules indicated that, relative to resident DCs, migratory DCs displayed a partially activated phenotype in the steady state. Furthermore, migratory DCs were refractory to stimulation by transient exposure to TLR agonists, as they failed to upregulate costimulatory molecules, secrete significant amounts of inflammatory cytokines, or induce differentiation of effector T cells. Together, these data show that transient systemic inflammation failed to break tolerance to the gastric autoantigen, as migratory DCs presenting the gastric autoantigen remain tolerogenic under such conditions, demonstrating the robust nature of peripheral tolerance.