Sullivan J A, Jankowska-Gan E, Hegde S, Pestrak M A, Agashe V V, Park A C, Brown M E, Kernien J F, Wilkes D S, Kaufman D B, Greenspan D S, Burlingham W J
Department of Surgery, University of Wisconsin, Madison, WI.
Department of Cell & Regenerative Biology, University of Wisconsin, Madison, WI.
Am J Transplant. 2017 Apr;17(4):944-956. doi: 10.1111/ajt.14097. Epub 2016 Dec 19.
T helper 17 (Th17)-dependent autoimmune responses can develop after heart or lung transplantation and are associated with fibro-obliterative forms of chronic rejection; however, the specific self-antigens involved are typically different from those associated with autoimmune disease. To investigate the basis of these responses, we investigated whether removal of regulatory T cells or blockade of function reveals a similar autoantigen bias. We found that Th17 cells specific for collagen type V (Col V), kα1-tubulin, and vimentin were present in healthy adult peripheral blood mononuclear cells, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1[V]), we compared Th17 cells from healthy donors with Th17 cells from Col V-reactive heart and lung patients. Although the latter responded well to α1(V) fragments and peptides in an HLA-DR-restricted fashion, Th17 cells from healthy persons responded in an HLA-DR-restricted fashion to fragments but not to peptides. Col V, kα1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, preexisting Th17 response that is MHC class II restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis.
在心脏或肺移植后，依赖辅助性T细胞17（Th17）的自身免疫反应可能会发生，并且与慢性排斥反应的纤维闭塞形式相关；然而，所涉及的特定自身抗原通常与自身免疫性疾病相关的自身抗原不同。为了研究这些反应的基础，我们调查了去除调节性T细胞或阻断其功能是否会揭示类似的自身抗原偏好。我们发现，在健康成人外周血单核细胞、脐带血和胎儿胸腺中存在针对V型胶原（Col V）、α1微管蛋白和波形蛋白的Th17细胞。使用Col V三螺旋区域（α1[V]）的合成肽和重组片段，我们将健康供体的Th17细胞与Col V反应性心脏和肺部疾病患者的Th17细胞进行了比较。尽管后者以HLA-DR限制的方式对α1（V）片段和肽有良好反应，但健康人的Th17细胞以HLA-DR限制的方式对片段有反应，而对肽没有反应。Col V、α1微管蛋白和波形蛋白是一种高度保守、迄今未知、预先存在的、受MHC II类限制的Th17反应的首选靶标。这些数据表明，心脏和肺移植后的自身免疫可能是由控制气道和血管稳态的内在机制失调引起的。
