Christian Kurts

Cross-presentation: a general mechanism for CTL immunity and tolerance

Abstract MHC class I-restricted presentation is usually associated with the processing of endogenous antigens. However, this restriction element can present antigens that do not originate within the presenting cells. Here, Francis Carbone and colleagues describe how such cross-presentation is critical for cytotoxic T-cell surveillance of peripheral antigens, both self and foreign, located outside the secondary lymphoid compartment.

Cutting Edge: Dendritic Cells Are Sufficient to Cross-Present Self-Antigens to CD8 T Cells In Vivo

The mechanism of cross-presentation enables professional APCs to induce CD8 T cell-mediated immune responses against exogenous Ags. Through this mechanism, APCs can induce either immunity against infectious pathogens or tolerance against self-Ag residing in extralymphatic locations. An unanswered question in this field concerns the identity of the cross-presenting APC. All major classes of professional APCs, particularly dendritic cells, macrophages, and B cells, have previously been shown to be able to cross-present Ags in vitro. In the present study, we have created transgenic mice where MHC class I expression is driven selectively in dendritic cells and provide direct in vivo evidence that dendritic cells are sufficient to cross-present exogenous self-Ags and induce Ag-specific cell division of CD8-positive T cells.

Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens

Summary: There is now convincing evidence that CD8+ T cells can be activated by professional antigen‐presenting ceils which present antigens derived from non‐lymphoid tissues in association with MHC class I molecules in the draining lymph nodes. This mechanism, referred to as cross‐presentation, enables the immune system to respond to those microorganisms that infect only non‐lymphoid tissues. Consistent with this view, cross‐presentation was found to focus on antigens expressed in high concentrations and those released from dying cells, which can be expected to result from viral infections. Recent evidence, however, demonstrates that high dose self antigens can be cross‐presented constitutively, resulting m the activation of autoreactive CD8+ T cells. This does not lead to auto‐immunity under physiologic conditions, but to CD95‐mediated deletion of the T cells. Cross‐presentation can thus engage a well‐defined pathway of antigen‐induced T‐cell death and purge the immune system of autoreactive CD8+ T cells. Low dose self antigens are not cross‐presented and are consequently ignored. The immune system therefore uses two strategies to avoid CD8+ T‐cell‐mediated autoimmunity in the periphery: deletion of autoreactive CD8+ T cells responding to high dose self antigens and ignorance of self antigens expressed at low concentrations.

Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells.

The cytoplasmic adaptor protein FADD is an essential component of the death-inducing signaling complexes (DISCs) that assemble when TNF receptor family members, such as Fas, are ligated. FADD inititates the proteolytic cascade that leads to apoptosis by binding to and promoting the autocatalytic activation of caspase-8 [1-4]. Surprisingly, FADD (but not caspase-8) is also required for T cells to proliferate upon their stimulation with mitogens [5-9]. Using transgenic mice expressing a dominant-negative mutant of FADD (FADD-DN), we show that functional FADD is required for T cells to proliferate in response to antigens in vivo as well as to mitogens in culture. The costimulation of wild-type and FADD-DN T cells with mitogens revealed that FADD-DN T cells have a cell-autonomous defect in intracellular signaling. In contrast to another study [6], p53 deficiency did not rescue mitogen-induced proliferation of FADD-DN T cells, and neither did enforced expression of the apoptosis inhibitor Bcl-2. Like wild-type T cells, FADD-DN T cells stimulated with mitogens mobilized intracellular calcium and activated members of the NF-kappaB transcription factor family as well as p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Therefore, FADD must act downstream of or in parallel to these signaling pathways.

Cross-presentation: inducing CD8 T cell immunity and tolerance

Abstract. The term cross-presentation denotes the presentation of exogenous (extracellular) antigens to T cells, particularly CD8 T cells. It permits professional antigen-presenting cells which have collected antigens in nonlymphoid tissues to activate naive CD8 T cells in the secondary lymphatic compartment. Thus it allows CD8 T cells to scan nonlymphoid tissues for pathogens without the need of migrating there themselves and may hence be critical for immune responses to tissue-tropic viruses. It may also be essential in the immune response to nonlymphoid tumors. In contrast to the induction of immunogenic responses to pathogens, cross-presentation of self-antigens leads to CD8 T cell tolerance by deletion of autoreactive CD8 T cells. The precise way in which the immune system distinguishes self from foreign is not known, but modification in the cross-presenting antigen-presenting cell, such as that achieved by CD4 T cell help or inflammatory signals, may play a critical role in this process. If the dose of the self-antigen or the avidity of the T cell receptor is too low, cross-presentation fails to remove autoreactive CD8 T cells. Ignoring the self-antigen, these cells recirculate through the secondary lymphatics, unless they are activated, for example, by a cross-reactive virus. Then autoimmunity may be triggered.

The use of carboxyfluorescein diacetate succinimidyl ester to determine the site, duration and cell type responsible for antigen presentation in vivo

This report examines the use of 5‐(and‐6)‐carboxyfluorescein diacetate succinimidyl ester (CFSE) to determine the site, duration and cell type responsible for antigen presentation in vivo. Evidence that CFSE‐labelled T cells can be used to determine where various types of antigens are presented, including auto‐antigens, oral antigens and cell‐associated foreign antigens, is provided. Using this technique, the length of time antigen is presented after acquisition by APC was measured. Finally, CFSE labelling was used to identify the origin of the APC responsible for different forms of antigen presentation.

The threshold for autoimmune T cell killing is influenced by B7‐1

The concept that naive CD4+ and CD8+ T cells require co‐stimulatory signals for activation and proliferation is well documented. Less clear is the need for co‐stimulation during the effector phase of the T cell response. Here we examined the influence of B7‐1 (CD80) during the effector phase of an autoimmune response to pancreatic islets using transgenic mouse lines which expressed B7‐1 in either all or only some of their β cells ( “confluent” or “patchy” RIP‐B7‐1 mice). Transgenic expression of B7‐1 in normal mouse islets that co‐expressed the pro‐inflammatory cytokine, IL‐2, resulted in early spontaneous autoimmunity. Islets with IL‐2 and “confluent” B7‐1 expression were destroyed whereas islets with IL‐2 and “patchy” B7‐1 expression showed selective killing of the B7‐1+ β cells. Islet‐reactive T cells, circulating in the RIP‐B7‐1/IL‐2 mice, rejected syngeneic islet grafts, but only if these expressed B7‐1. Introduction of the B7‐1 transgene into the nonobese diabetic (NOD) genetic background likewise resulted in early spontaneous autoimmunity, but splenocytes from the diabetic animals could only transfer diabetes to NOD scid recipients that expressed B7‐1 on their β cells. In both these transgenic models, therefore, islet destruction required continuous B7‐1 expression by target β cells. Thus, although the normal repertoire contains T cells with potential islet reactivity, these T cells remain harmless because parenchymal cells like the β cell cannot normally express B7‐1. Our results also have implications for tumor immunotherapy in that the ability of T cells to kill poorly immunogenic targets may be dependent upon B7‐1 expression by the target cell itself.