Robust antigen specific th17 T cell response to group A Streptococcus is dependent on IL-6 and intranasal route of infection.
Robust antigen specific th17 T cell response to group A Streptococcus is dependent on IL-6 and intranasal route of infection.
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DOI：
10.1371/journal.ppat.1002252
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发表时间：
2011-09
期刊：
影响因子：
6.7
通讯作者：
Cleary PP
中科院分区：
文献类型：
--
作者：
Dileepan T;Linehan JL;Moon JJ;Pepper M;Jenkins MK;Cleary PP
A组链球菌(GAS，化脓性链球菌)可引起多种临床症状，从咽炎到自身免疫性疾病。近年来，多肽主要组织相容性复合体II类(PMHCII)四聚体已成为一种高度敏感的方法，可用于定量检测pMHCII特异性的CD4+辅助T细胞，并评估其在保护性免疫和由特定细菌病原体引起的自身免疫并发症中的作用。代替鉴定由GAS表达的免疫优势肽，将代理肽(2W)与GAS表面高表达的M1蛋白融合，以允许深入分析表达I-AbMHCII分子的C57BL/6小鼠的CD4+辅助T细胞反应。鼻腔接种GAS-2W后，在鼻腔相关淋巴组织中检测到抗原特异性的2W：I-AbCD+T细胞，产生IL-17A或IL-17A和干扰素-γ，如果感染复发。主要的Th1 7应答也依赖于鼻腔接种途径；静脉或皮下接种主要产生干扰素-γ+2W：I-Ab+CD4+T细胞。2W：I-Ab特异性T细胞产生IL-17A的能力和小鼠存活感染的能力依赖于天然的细胞因子IL-6。感染后存活的IL-6缺陷小鼠成为长期携带者，尽管存在大量产生干扰素-γ的2W：I-AbCD4+T细胞。我们的结果表明，产生IL-17和干扰素-γ的CD+T细胞之间的失衡可能是人类气体携带的原因之一。A组链球菌(GAS)导致许多不同的情况，从链球菌咽喉、食肉疾病到涉及心脏的感染后并发症。在这里，我们使用了一种新的技术来研究小鼠模型中针对GAS感染的CD4+T细胞免疫反应。我们首先产生了一种表达特定表位(2W)-M蛋白融合的重组GAS菌株，并将其用于鼻腔接种小鼠。用2W-MHC-II四聚体分析多肽特异性的CD4+T细胞。这项技术使我们能够探测到抗原特异性的CD4+T细胞反应的新深度和确定性。感染诱导了强大的2W特异性Th17细胞反应，这种反应依赖于感染途径IL-6，并且不依赖于超抗原。IL-6-/-小鼠对鼻腔感染非常敏感。然而，那些幸存下来的人成为了免疫携带者，无法从NALT中清除链球菌。此外，多重感染产生了IL-17+干扰素-γ+双阳性T细胞群，已知与人类自身免疫性疾病有关，并直接导致啮齿动物模型的自身免疫性病理。我们的结果为了解链球菌性咽炎的两种重要后果提供了新的方向，一种是非常常见的免疫携带者状态，另一种是涉及自身免疫并发症的罕见状态。
Group A streptococcus (GAS, Streptococcus pyogenes) is the cause of a variety of clinical conditions, ranging from pharyngitis to autoimmune disease. Peptide-major histocompatibility complex class II (pMHCII) tetramers have recently emerged as a highly sensitive means to quantify pMHCII-specific CD4+ helper T cells and evaluate their contribution to both protective immunity and autoimmune complications induced by specific bacterial pathogens. In lieu of identifying an immunodominant peptide expressed by GAS, a surrogate peptide (2W) was fused to the highly expressed M1 protein on the surface of GAS to allow in-depth analysis of the CD4+ helper T cell response in C57BL/6 mice that express the I-Ab MHCII molecule. Following intranasal inoculation with GAS-2W, antigen-experienced 2W:I-Ab-specific CD4+ T cells were identified in the nasal-associated lymphoid tissue (NALT) that produced IL-17A or IL-17A and IFN-γ if infection was recurrent. The dominant Th17 response was also dependent on the intranasal route of inoculation; intravenous or subcutaneous inoculations produced primarily IFN-γ+ 2W:I-Ab+ CD4+ T cells. The acquisition of IL-17A production by 2W:I-Ab-specific T cells and the capacity of mice to survive infection depended on the innate cytokine IL-6. IL-6-deficient mice that survived infection became long-term carriers despite the presence of abundant IFN-γ-producing 2W:I-Ab-specific CD4+ T cells. Our results suggest that an imbalance between IL-17- and IFN-γ-producing CD4+ T cells could contribute to GAS carriage in humans. Group A streptococcus (GAS) causes many different conditions, ranging from strep throat, flesh eating disease to post infectious complications involving the heart. Here, we used a novel technique to study the CD4+ T cell immune response against GAS infection in a mouse model. We first generated a recombinant GAS strain that expresses a specific epitope (2W) - M protein fusion and used this to intranasally inoculate mice. Peptide specific CD4+ T cells were concentrated and analyzed using 2W-MHC-II tetramers. This technology allowed us to probe the antigen specific CD4+ T cell response to new depths and certainty. Infection induced a robust 2W-specific Th17 cell response, which was dependent on the route of infection, IL-6, and was independent of superantigens. IL-6-/- mice were exquisitely susceptible to intranasal infection. However, those that survived became immune carriers, unable to clear streptococci from NALT. Further, multiple infections generated an IL-17+ IFN-γ+ double positive population of CD4+ T cells that are known to be associated with autoimmune disease in humans and directly responsible for autoimmune pathology in rodent models. Our results provide a new direction for understanding two important consequences of streptococcal pharyngitis, the very common immune carrier state, and the rarer state involving autoimmune complications.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
白介素17a介导获得的对肺炎球菌定殖的免疫力。
影响因子：
6.7
作者：
Lu, Ying-Jie;Gross, Jane;Bogaert, Debby;Finn, Adam;Bagrade, Linda;Zhang, Qibo;Kolls, Jay K.;Srivastava, Amit;Lundgren, Anna;Forte, Sophie;Thompson, Claudette M.;Harney, Kathleen F.;Anderson, Porter W.;Lipsitch, Marc;Malley, Richard
通讯作者：
Malley, Richard
抗原注射后进入排水淋巴结的CD4+ T细胞参与了主要反应并成为中央记忆细胞。
DOI：
10.1084/jem.20051954
发表时间：
2006-04-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Catron DM;Rusch LK;Hataye J;Itano AA;Jenkins MK
通讯作者：
Jenkins MK
影响因子：
32.4
作者：
Moon, James J.;Chu, H. Hamlet;Jenkins, Marc K.
通讯作者：
Jenkins, Marc K.
DOI：
10.1007/978-0-387-73960-1_3
发表时间：
2008-01-01
期刊：
HOT TOPICS IN INFECTION AND IMMUNITY IN CHILDREN IV
影响因子：
--
作者：
Cunningham, Madeleine W.
通讯作者：
Cunningham, Madeleine W.