Coronary Arteries from Human Cardiac Allografts with Chronic Rejection Contain Oligoclonal T Cells: Persistence of Identical Clonally Expanded TCR Transcripts from the Early Post-Transplantation Period (Endomyocardial Biopsies) to Chronic Rejection (Coronary Arteries)

Abstract

Chronic cardiac allograft rejection presents pathologically as graft arteriosclerosis (GA) characterized by recipient T cell and monocyte infiltration. To determine whether oligoclonal T cells are present in coronary arteries of cardiac allografts from patients with GA, we conducted sequencing analysis of β-chain TCR transcripts from these explanted coronary arteries using the nonpalindromic adaptor-PCR. Substantial proportions of identical β-chain TCR transcripts in three of five patients were observed, clearly demonstrating the presence of oligoclonal T cells. TCR transcripts from the arteries of two other patients were relative heterogeneous. High proportions of identical CDR3 β-chain TCR motifs were found in each patient. GENEBANK/EMBL/SWISS PROT database comparison of all sequences revealed that these β-chain TCR transcripts were novel. Using Vβ-specific PCR (independent amplification), we found in patient GA03 that the TCR transcript that was clonally expanded in the left anterior descending artery after nonpalindromic adaptor-PCR was also clonally expanded in the right coronary artery of the same allograft. These results demonstrate that this TCR transcript was clonally expanded at different anatomic sides of the cardiac allograft in a systemic manner. In two patients identical β-chain TCR transcripts that were found to be clonally expanded in the coronary arteries of their explanted cardiac allografts were also found to be clonally explanted in endomyocardial biopsies collected 17 and 21 mo earlier from each patient. The presence of oligoclonal populations of T cells in the rejected graft suggest that these T cells have undergone specific Ag-driven proliferation and clonal expansion early on within the graft and persist throughout the post-transplantation period.

Interferon-γ Axis in Graft Arteriosclerosis

“…Little is known regarding the unique identity of leukocytes in GA. In a related pair of studies, sequencing analysis of T-cell receptor transcripts from the coronary arteries of a limited number of patients with GA demonstrated oligoclonal populations of T cells in the majority and relatively heterogeneous populations of T cells in the minority of explanted hearts with severe GA. 14,15 In some patients, from whom the relevant specimens were available, the same clones of T cells were found in multiple conduit arteries, as well as in endomyocardial biopsies of acutely rejecting parenchyma from years earlier.…”

The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells

“…To explore whether these homologies occurred by chance, the CDR3 regions of 158 CAS clones and a disease control of 116 T cell clones obtained from the kidneys of individuals with lupus nephritis were each compared with the corresponding region of both 223 productively rearranged graft-arteriosclerosis clones in GenBank (30) and 99 atherosclerosis clones (18). Only the 10 aa match of Set10 was found, with no matches between CAS and atherosclerosis, or between the renal T cells and either atherosclerosis or graft arteriosclerosis.…”

Is systemic sclerosis an antigen‐driven T cell disease?

“…The nonpalindromic PCR method was developed in our laboratory specifically for the amplification of transcripts with an unknown or variable 5Ј end, such as the TCRs and immunoglobulins (55)(56)(57)(58). The amplified transcripts were cloned and sequenced.…”