An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA-Restricted T Cell Responses.
An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA-Restricted T Cell Responses.
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抑制关节炎和诱导 Treg 细胞的 CD4 T 细胞表位在 HLA 限制性 T 细胞反应中发挥作用。
DOI：
10.1002/art.39444
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Broere,Femke
中科院分区：
文献类型：
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作者：
deWolf,Charlotte;vanderZee,Ruurd;denBraber,Ineke;Glant,Tibor;Maillère,Bernard;Favry,Emmanuel;vanLummel,Menno;Koning,Frits;Hoek,Aad;Ludwig,Irene;vanEden,Willem;Broere,Femke
我们之前发现，分枝杆菌Hsp70衍生肽B29诱导B29特异性Treg细胞通过交叉识别其哺乳动物Hsp70同源物来抑制实验性小鼠关节炎。本研究的目的是在人类主要组织相容性复合体（MHC）分子的背景下表征B29结合和特异性CD4+ T细胞反应。方法采用竞争结合法检测肽B29及其哺乳动物同源物与HLA分子的结合。我们评估了B29免疫对hla - dq8转基因蛋白多糖诱导的关节炎小鼠的影响，然后用B29体外再刺激来检测T细胞反应。使用人外周血单个核细胞研究具有免疫调节潜能的B29特异性T细胞的存在。结果B29肽对多种HLA-DR和HLA-DQ分子的结合亲和力为高至中等，包括与类风湿关节炎高度相关的分子。这种结合被认为是功能性的，因为B29免疫可抑制hla - dq8转基因小鼠的关节炎和T细胞反应。在人类中，我们证明了B29特异性CD4+ T细胞的存在和扩增，这些细胞与哺乳动物同源物发生交叉反应。利用B29或哺乳动物同源物mB29b特异性的HLA-DR4 +四聚体，我们发现在体外B29刺激后，交叉反应T细胞扩增，特别是人类FoxP3+ CD4+CD25+ T细胞群。结论B29诱导的Treg细胞反应在人MHC环境下具有保守的特异性和功能性。基于这些发现，将B29的实验结果转化为临床免疫调节治疗方法的途径已经触手可及。
ObjectiveWe previously showed that mycobacterial Hsp70‐derived peptide B29 induced B29‐specific Treg cells that suppressed experimental arthritis in mice via cross‐recognition of their mammalian Hsp70 homologs. The aim of the current study was to characterize B29 binding and specific CD4+ T cell responses in the context of human major histocompatibility complex (MHC) molecules.MethodsCompetitive binding assays were performed to examine binding of peptide B29 and its mammalian homologs to HLA molecules. The effect of B29 immunization in HLA–DQ8–transgenic mice with proteoglycan‐induced arthritis was assessed, followed by ex vivo restimulation with B29 to examine the T cell response. Human peripheral blood mononuclear cells were used to investigate the presence of B29‐specific T cells with immunoregulatory potential.ResultsThe binding affinity of the B29 peptide was high to moderate for multiple HLA–DR and HLA–DQ molecules, including those highly associated with rheumatoid arthritis. This binding was considered to be functional, because B29 immunization resulted in the suppression of arthritis and T cell responses in HLA–DQ8–transgenic mice. In humans, we demonstrated the presence and expansion of B29‐specific CD4+ T cells, which were cross‐reactive with the mammalian homologs. Using HLA–DR4+ tetramers specific for B29 or the mammalian homolog mB29b, we showed expansion of cross‐reactive T cells, especially the human FoxP3+ CD4+CD25+ T cell population, after in vitro stimulation with B29.ConclusionThese results demonstrated a conserved fine specificity and functionality of B29‐induced Treg cell responses in the context of the human MHC. Based on these findings, a path for translation of the experimental findings for B29 into a clinical immunomodulatory therapeutic approach is within reach.