Mitchell Angela M, Kaiser Ylva, Falta Michael T, Munson Daniel J, Landry Laurie G, Eklund Anders, Nakayama Maki, Slansky Jill E, Grunewald Johan, Fontenot Andrew P
Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
J Immunol. 2017 Oct 1;199(7):2279-2290. doi: 10.4049/jimmunol.1700570. Epub 2017 Aug 21.
Sarcoidosis is a granulomatous disease that primarily affects the lungs and is characterized by an accumulation of CD4 T cells in the bronchoalveolar lavage (BAL). Previous work has indicated that HLA-DRB1*03:01 (DR3) patients diagnosed with the acute form of the disease, Löfgren's syndrome (LS), have an accumulation of CD4 T cells bearing TCRs using TRAV12-1 (formerly AV2S3). However, the importance of these α-chains in disease pathogenesis and the paired TCRβ-chain remains unknown. This study aimed to identify expanded αβTCR pairs expressed on CD4 T cells derived from the BAL of DR3 LS patients. Using a deep-sequencing approach, we determined TCRα- and TCRβ-chain usage, as well as αβTCR pairs expressed on BAL CD4 T cells from LS patients. TRAV12-1 and TRBV2 (formerly BV22) were the most expanded V region gene segments in DR3 LS patients relative to control subjects, and TRAV12-1 and TRBV2 CDR3 motifs were shared among multiple DR3 LS patients. When assessing αβTCR pairing, TRAV12-1 preferentially paired with TRBV2, and these TRAV12-1/TRBV2 TCRs displayed CDR3 homology. These findings suggest that public CD4 TCR repertoires exist among LS patients and that these T cells are recognizing the putative sarcoidosis-associated Ag(s) in the context of DR3.
结节病是一种主要影响肺部的肉芽肿性疾病，其特征是支气管肺泡灌洗（BAL）中CD4 T细胞积聚。先前的研究表明，被诊断为急性结节病形式即 Löfgren 综合征（LS）的 HLA-DRB1*03:01（DR3）患者，存在使用TRAV12-1（以前称为AV2S3）的携带TCR的CD4 T细胞积聚。然而，这些α链在疾病发病机制中的重要性以及配对的TCRβ链仍然未知。本研究旨在鉴定源自DR3 LS患者BAL的CD4 T细胞上表达的扩增αβTCR对。使用深度测序方法，我们确定了TCRα和TCRβ链的使用情况，以及LS患者BAL CD4 T细胞上表达的αβTCR对。相对于对照受试者，TRAV12-1和TRBV2（以前称为BV22）是DR3 LS患者中扩增最多的V区基因片段，并且多个DR3 LS患者之间共享TRAV12-1和TRBV2 CDR3基序。在评估αβTCR配对时，TRAV12-1优先与TRBV2配对，并且这些TRAV12-1/TRBV2 TCR显示出CDR3同源性。这些发现表明LS患者中存在公共CD4 TCR谱系，并且这些T细胞在DR3背景下识别假定的结节病相关抗原。
