Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides.
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.
Macconi
Daniela
D
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.
Chiabrando
Chiara
C
Schiarea
Silvia
S
Aiello
Sistiana
S
Cassis
Linda
L
Gagliardini
Elena
E
Noris
Marina
M
Buelli
Simona
S
Zoja
Carla
C
Corna
Daniela
D
Mele
Caterina
C
Fanelli
Roberto
R
Remuzzi
Giuseppe
G
Benigni
Ariela
A
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation; D039521:CD11c Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007108:Immune Tolerance; D007668:Kidney / Q000276:immunology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D011507:Proteinuria / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000418:Albumins; D039521:CD11c Antigen; D015395:Histocompatibility Antigens Class I; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex