Class I–restricted Cross-Presentation of Exogenous Self-Antigens Leads to Deletion of Autoreactive CD8+ T Cells

Abstract

In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8+ T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8+ T cells (OT-I cells) into rat insulin promoter–membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the β cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I–restricted cross-presentation of exogenous OVA on a bone marrow–derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow–derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8+ T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

“…Male NOD mice, for example, show a stable periinsulitis that rarely progresses to IDDM. This fact is in line with reports showing that crosspresentation of peripheral antigens in general, and of antigens expressed as a transgene on beta cells in particular [36,37,38,39], could preferentially lead to the induction of tolerance rather than to autoimmunity. The parameters driving the decision between tolerance and immunity, that is, the transition from harmless insulitis to beta-cell killing, are still poorly understood.…”

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

“…DC are now implicated in the regulation of the responses they initiate and in the maintenance of tolerance to self components [1,2]. DC are involved in both central tolerance in the thymus [3,4] and in peripheral tolerance of self-reactive T cells that have escaped intra-thymic deletion [2,[5][6][7]. The activation or 'maturation' state of the DC is believed to determine the balance between tolerance and immunity.…”

Mini‐review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross‐priming and direct priming?

“…In a series of landmark studies, Heath and colleagues showed that the level of expressed protein, in their case OVA expressed under the rat insulin promoter (RIP), decides whether enough protein is ingested by DC to alert CD8 + CTL precursors for response induction (crosspriming) or tolerance induction (cross-tolerance), depending on the activation state of the DC [25]. In this model CTL priming depends on OVA-specific CD4 + T cells that need to activate the DC that are crosspresenting MHC class I peptides, to achieve crosspriming ("license to kill").…”

“…A large body of evidence shows that T cells die or become anergic if they do not receive these costimulatory and survival signals from DC [25,32,35,[56][57][58][59]. This is highly proper, because this places the DC in the middle of an intricate cellular network that ensures T cell death/anergy (in non-inflammatory conditions including most tumors) or survival (in the presence of dangerous pathogens).…”

“…What we do not agree with, however, is to equate this with inefficient cross-presentation. Abundant evidence shows that many different mechanisms operate to efficiently process exogenous protein antigens from tissues, including tumors, for presentation by MHC class I molecules [17,25,26,35,56,57].…”