Self-peptides prolong survival in murine autoimmunity via reduced IL-2/IL-7-mediated STAT5 signaling, CD8 coreceptor, and V alpha 2 down-regulation.
Self-peptides prolong survival in murine autoimmunity via reduced IL-2/IL-7-mediated STAT5 signaling, CD8 coreceptor, and V alpha 2 down-regulation.
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DOI：
10.4049/jimmunol.0900793
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发表时间：
2009-09-01
期刊：
影响因子：
--
通讯作者：
Katz SI
中科院分区：
文献类型：
--
作者：
Gutermuth J;Nograles KE;Miyagawa F;Nelson E;Cho YH;Katz SI
虽然B细胞和CD 4 T细胞的致病作用已被广泛研究，但对CD 8 T细胞在自身免疫和自身耐受中的作用知之甚少。为了评估CD 8 T细胞在自身免疫中的作用及其使用自身肽的调节，我们利用在角蛋白-14启动子控制下表达可溶性卵清蛋白（sOVA）的小鼠。当sOVA-小鼠与OT-I小鼠杂交时发生自发性自身免疫，OT-I小鼠的CD 8 T细胞携带对OVA 257 -264-肽（OVAp）具有特异性的Vα2/Vβ5转基因T细胞受体。83%的OVA/OT-I小鼠在出生后的前两周内死于多器官炎症。相比之下，预防性或治疗性OVAp注射诱导存活率的剂量依赖性增加。健康存活者外周血CD 8 T细胞、CD 8辅助受体和Vα2表达减少。此外，来自健康小鼠的CD 8 T细胞是无反应性的，并且不能被外源性IL-2激活。通过STAT 5途径阻断IL-2/IL-7信号传导为CD 8辅助受体的低表面表达和IL-2未能打破CD 8 T细胞无反应性提供了基础。因此，可溶性T细胞受体配体在这些sOVA/OT-I小鼠中触发了多种耐受机制，使得这种治疗方法成为调节人类自身免疫性疾病的潜在范例。
While the pathogenic role of B cells and CD4 T cells has been studied extensively, less is known about the role of CD8 T cells in autoimmunity and self-tolerance. To evaluate the role of CD8 T cells in autoimmunity and its modulation using self-peptides, we utilized mice expressing soluble ovalbumin (sOVA) under control of the keratin-14 promoter. Spontaneous autoimmunity occurred when sOVA-mice were crossed with OT-I mice, whose CD8 T cells carry a Vα2/Vβ5-transgenic T cell receptor with specificity for the OVA257-264-peptide (OVAp). 83% of OVA/OT-I mice died during the first two weeks of life due to multiple-organ inflammation. In contrast, preventive or therapeutic OVAp injections induced a dose-dependent increase in survival. Healthy survivors exhibited reductions in peripheral CD8 T cells, CD8-coreceptor- and Vα2-expression. Furthermore, CD8 T cells from healthy mice were anergic and could not be activated by exogenous IL-2. A block in IL-2/IL-7 signaling via the STAT5-pathway provided the basis for low surface expression of the CD8-coreceptor and failure of IL-2 to break CD8 T cell anergy. Thus, soluble T cell receptor ligand triggered multiple tolerance mechanisms in these sOVA/OT-I mice, making this treatment approach a potential paradigm for modulating human autoimmune diseases.
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DOI：
10.1084/jem.20001021
发表时间：
2002-03-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Blattman JN;Antia R;Sourdive DJ;Wang X;Kaech SM;Murali-Krishna K;Altman JD;Ahmed R
通讯作者：
Ahmed R
影响因子：
30.5
作者：
McGargill, MA;Derbinski, JM;Hogquist, KA
通讯作者：
Hogquist, KA
DOI：
10.1097/med.0b013e32825a673b
发表时间：
2007-08-01
期刊：
Current opinion in endocrinology, diabetes, and obesity
影响因子：
--
作者：
Haller, Michael J;Gottlieb, Peter A;Schatz, Desmond A
通讯作者：
Schatz, Desmond A
影响因子：
4.4
作者：
Bercovici, N;Heurtier, A;Liblau, R
通讯作者：
Liblau, R
影响因子：
4.2
作者：
Achenbach, Peter;Barker, Jennifer;Bonifacio, Ezio
通讯作者：
Bonifacio, Ezio