TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis
TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis
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DOI：
10.4049/jimmunol.178.6.3466
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Kopf, Manfred
中科院分区：
文献类型：
--
作者：
Marsland, Benjamin J.;Nembrini, Chiara;Kopf, Manfred
丝氨酸/苏氨酸激酶，蛋白激酶C-θ（PKC-θ），在Th 2细胞的活化和分化中起核心作用，而在CD 4（+）和CD 8（+）抗病毒应答中是多余的。然而，最近的证据表明，PKC-θ可能是某些T细胞驱动的自身免疫反应所必需的。我们研究了PKC-θ在诱导自身免疫性心肌炎中的作用，该心肌炎由科萨基B3病毒感染或α-肌球蛋白/CFA免疫诱导（实验性自身免疫性心肌炎（EAM））。PKC-theta缺陷小鼠没有出现EAM，表现为炎症细胞浸润心脏受损、CD 4 + T细胞IL-17产生减少以及缺乏肌球蛋白特异性Ab反应。相比之下，PKC-θ在早期和晚期科萨基病毒诱导的心肌炎中不是必需的。我们试图找到替代途径的免疫刺激，可能调和的差异要求PKC-θ在这两种疾病模型。我们发现全身给予TLR配体CpG可恢复PKC-θ缺陷小鼠的EAM。CpG可以直接作用于表达TLR 9的T细胞以恢复增殖和上调Bcl-x（L），但Th 17细胞分化需要外源性IL-6和TGF-β。总之，这些结果表明TLR介导的T细胞活化可以直接克服对PKC-θ信号传导的需要，并且与树突状细胞衍生的细胞因子环境相结合，可以促进自身免疫的发展。
The serine/threonine kinase, protein kinase C-theta (PKC-theta), plays a central role in the activation and differentiation of Th2 cells while being redundant in CD4(+) and CD8(+) antiviral responses. Recent evidence indicates that PKC-theta may however be required for some T cell-driven autoimmune responses. We have investigated the role of PKC-theta in the induction of autoimmune myocarditis induced by either Coxsackie B3 virus infection or immunization with alpha-myosin/CFA (experimental autoimmune myocarditis (EAM)). PKC-theta-deficient mice did not develop EAM as shown by impaired inflammatory cell infiltration into the heart, reduced CD4+ T cell IL-17 production, and the absence of a myosin-specific Ab response. Comparatively, PKC-theta was not essential for both early and late-phase Coxsackie virus-induced myocarditis. We sought to find alternate pathways of immune stimulation that might reconcile the differential requirements for PKC-theta in these two disease models. We found systemic administration of the TLR ligand CpG restored EAM in PKC-theta-deficient mice. CpG could act directly upon TLR9-expressing T cells to restore proliferation and up-regulation of Bcl-x(L), but exogenous IL-6 and TGF-beta was required for Th17 cell differentiation. Taken together, these results indicate that TLR-mediated activation of T cells can directly overcome the requirement for PKC-theta signaling and, combined with the dendritic cell-derived cytokine milieu, can promote the development of autoimmunity.