Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.
Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.
复制标题
作者：
1型糖尿病(T1D)的一个主要治疗目标是诱导T细胞自身抗原特异性耐受。这可能会抑制那些有患T1D风险的人，以及那些接受胰岛替代或再生治疗的既往疾病患者的自身免疫力。由于对人类自身反应性T细胞反应的功能研究主要局限于外周血来源的T细胞，因此尚不清楚外周T细胞库中T细胞渗入胰岛的代表性。我们对胰岛素T细胞谱系的了解来自于对胰岛素炎的组织学和免疫组织化学分析，在人类白细胞抗原(HLA)-A2+捐赠者的胰岛中原位鉴定自身反应性CD8+T细胞，以及从患有T1D的单一捐赠者的胰岛中分离和鉴定DQ8和DQ2-DQ8异源二聚体限制的、胰岛素原反应性的CD4+T细胞。在这里，我们提出了对总共236个CD4+和CD8+T细胞系中的50个的分析，这些细胞系是从单独的亲手挑选的胰岛或直接从9名T1D捐赠者的亲手挑选的分散的胰岛克隆中培养出来的。这些T细胞系和克隆中有17个与广泛研究的天然胰岛抗原和翻译后修饰的多肽发生反应。这些研究表明，在患有T1D的患者中，存在各种胰岛浸润性、胰岛自身抗原反应性T细胞，这些数据对成功的免疫治疗的设计具有一定的意义。
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood–derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8+ T cells in situ, in islets of human leukocyte antigen (HLA)-A2+ donors and isolation and identification of DQ8 and DQ2–DQ8 heterodimer–restricted, proinsulin-reactive CD4+ T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4+ and CD8+ T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.