Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Sci Transl Med. 2013 Jun 5;5(188):188ra74. doi: 10.1126/scitranslmed.3005452.
Acute graft-versus-host disease (aGVHD) results from a robust response of donor T cells transferred during hematopoietic stem cell transplantation (HSCT) to allogeneic peptide-major histocompatibility complex antigens. Previous investigations have not identified T cell subsets that selectively mediate either protective immunity or pathogenic alloreactivity. We demonstrate that the small subset of peripheral T cells that naturally express two T cell receptors (TCRs) on the cell surface contributes disproportionately to aGVHD in patients after allogeneic HSCT. Dual TCR T cells from patients with aGVHD demonstrate an activated phenotype and produce pathogenic cytokines ex vivo. Dual receptor clones from a patient with symptomatic aGVHD responded specifically to mismatched recipient human leukocyte antigens (HLAs), demonstrating pathologic alloreactivity. Human dual TCR T cells are strongly activated and expanded by allogeneic stimulation in vitro, and disproportionately contribute to the repertoire of T cells recognizing both major (HLA) and minor histocompatibility antigens, providing a mechanism for their observed activity in vivo in patients with aGVHD. These results identify dual TCR T cells as a target for focused analysis of a T cell subset mediating GVHD and as a potential prognostic indicator.
急性移植物抗宿主病（aGVHD）是由于造血干细胞移植（HSCT）期间转移的供体 T 细胞对异体肽-主要组织相容性复合体抗原产生强烈反应而引起的。以前的研究尚未确定选择性介导保护性免疫或致病性同种异体反应性的 T 细胞亚群。我们证明，在同种异体 HSCT 后，自然表达细胞表面两种 T 细胞受体（TCR）的外周 T 细胞的一小部分不成比例地导致 aGVHD。来自 aGVHD 患者的双 TCR T 细胞表现出激活的表型，并在体外产生致病性细胞因子。来自有症状 aGVHD 患者的双受体克隆特异性地对不合受体人类白细胞抗原（HLAs）作出反应，表现出病理性同种异体反应性。人双 TCR T 细胞在体外通过同种异体刺激被强烈激活和扩增，并不成比例地有助于识别主要（HLA）和次要组织相容性抗原的 T 细胞库，为其在 aGVHD 患者体内的观察到的活性提供了机制。这些结果将双 TCR T 细胞鉴定为靶向分析介导 GVHD 的 T 细胞亚群的目标，并作为潜在的预后指标。
