The Cross-Priming Capacity and Direct Presentation Potential of an Autoantigen Are Separable and Inversely Related Properties

Abstract

We investigated whether a prevalent epitope of the β-cell–specific autoantigen islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP206–214) reaches regional Ag-presentation pathways via unprocessed polypeptide chains, as free IGRP206–214 peptide or via preformed IGRP206–214/Kd complexes. This was accomplished by expressing bacterial artificial chromosome transgenes encoding wild-type (stable) or ubiquitinated (unstable) forms of IGRP in IGRP-deficient NOD mice carrying MHC class I–deficient β-cells, dendritic cells, or B cells. We investigated the ability of the pancreatic lymph nodes of these mice to prime naive IGRP206–214-reactive CD8+ T cells in vivo, either in response to spontaneous Ag shedding, or to synchronized forms of β-cell necrosis or apoptosis. When IGRP was made unstable by targeting it for proteasomal degradation within β-cells, the cross-priming, autoimmune-initiating potential of this autoantigen (designated autoantigenicity) was impaired. Yet at the same time, the direct presentation, CTL-targeting potential of IGRP (designated pathogenicity) was enhanced. The appearance of IGRP206–214 in regional Ag-presentation pathways was dissociated from transfer of IGRP206–214 or IGRP206–214/Kd from β cells to dendritic cells. These results indicate that autoantigenicity and pathogenicity are separable and inversely related properties and suggest that pathogenic autoantigens, capable of efficiently priming CTLs while marking target cells for CTL-induced killing, may have a critical balance of these two properties.

The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules

“…However, there is some data that suggest that GAP junctions and trogocytosis are unlikely to be the major mechanisms underlying XPT in vivo, at least in many situations. In one set of experiments, donor cells with large numbers of antigen-MHC I complexes but low levels of intact antigen failed to cross-prime responses (63–65). Therefore, peptide or peptide-MHC I complexes aren’t dominant mechanisms driving XPT in vivo, at least in these systems.…”

Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity

“…This ability of LiNKTR1 cells to suppress pancreatic autoimmunity is due to two facts, (i) that the pancreatic and portal/celiac lymph nodes simultaneously drain both the liver and the pancreas; and (ii) that the re-programmed LiNKTR1 cells (or the Breg cells arising downstream of LiNKTR1 cells) can suppress antigen presentation and autoreactive T-cell activation at both sites. Specifically, IGRP 206-214 -specific 8.3-CD8 + T cells (recognizing an epitope from an autoantigen that is exclusively expressed in pancreatic beta cells) proliferate in both lymph node types (but not elsewhere 57 ) and αGalCer/CD1d-NP therapy effectively blunted this in vivo proliferative response. These observations are consistent with two additional observations: (i) LiNKTR1cells from αGalCer/CD1d-NP-treated mice suppressed the ability of normal liver KCs and liver-draining CD11b + APCs to trigger 8.3-CD8 + T-cell activation in vitro; and (ii) KC and lymph node-derived CD11b + cells from αGalCer/CD1d-NP-treated mice displayed impaired antigen-presentation and pro-inflammatory capabilities ex vivo.…”