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Proteasomal Processing of Albumin by Renal Dendritic Cells Generates Antigenic Peptides

2008; American Society of Nephrology; Volume: 20; Issue: 1 Linguagem: Inglês

10.1681/asn.2007111233

1533-3450

Daniela Macconi, Chiara Chiabrando, Silvia Schiarea, Sistiana Aiello, Linda Cassis, Elena Gagliardini, Marina Noris, Simona Buelli, Carla Zoja, Daniela Corna, Caterina Mele, Roberto Fanelli, Giuseppe Remuzzi, Ariela Benigni,

T-cell and B-cell Immunology

The role of dendritic cells (DC) that accumulate in the renal parenchyma of non-immune-mediated proteinuric nephropathies is not well understood. Under certain circumstances, DC capture immunologically ignored antigens, including self-antigens, and present them within MHC class I, initiating an autoimmune response. We studied whether DC could generate antigenic peptides from the self-protein albumin. Exposure of rat proximal tubular cells to autologous albumin resulted in its proteolytic cleavage to form an N-terminal 24-amino acid peptide (ALB1-24). This peptide was further processed by the DC proteasome into antigenic peptides that had binding motifs for MHC class I and were capable of activating syngeneic CD8+ T cells. In vivo, the rat five-sixths nephrectomy model allowed the localization and activation of renal DC. Accumulation of DC in the renal parenchyma peaked 1 wk after surgery and decreased at 4 wk, concomitant with their appearance in the renal draining lymph nodes. DC from renal lymph nodes, loaded with ALB1-24, activated syngeneic CD8+ T cells in primary culture. The response of CD8+ T cells of five-sixths nephrectomized rats was amplified with secondary stimulation. In contrast, DC from renal lymph nodes of five-sixths nephrectomized rats treated with the proteasomal inhibitor bortezomib lost their capacity to stimulate CD8+ T cells in primary and secondary cultures. These data suggest that albumin can be a source of potentially antigenic peptides upon renal injury and that renal DC play a role in processing self-proteins through a proteasome-dependent pathway.