Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

Abstract

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

Blood‐stage Plasmodium berghei infection leads to short‐lived parasite‐associated antigen presentation by dendritic cells

“…Inhibition of MHC II-restricted presentation makes sense, since the mechanism underlying down-regulation of cross-presentation was implicated to be a shut-down in phagocytosis caused by DC activation, and this mechanism would be expected to affect both MHC I-and II-restricted presentation of antigens captured by phagocytosis. Here, we provide direct evidence that phagocytosis is impaired as P. berghei infection progresses, supporting earlier work that showed a similar shut-down in phagocytosis after TLR-ligand-mediated global DC activation [13]. These findings suggest that P. berghei infection leads to delivery of activating signals to DC, which then mature to a stage unable to capture new antigens.…”

“…Presentation of cell-associated OVA to CD4 1 OT-II cells was assessed 60 h later by measuring OT-II proliferation in the spleen by flow cytometry. Similar to our previous findings for crosspresentation to CD8 1 OT-I cells [13], MHC II-restricted presentation of cell-associated OVA to CD4 1 OT-II cells was efficient when the antigen was injected into naïve mice or within 1 day of infection, but rapidly declined thereafter (Fig. 1).…”

“…Data are representative of two experiments (n 5 4); statistically different mean values are indicated by asterisks ( ÃÃ po0.01, ÃÃÃ po0.001). Please note that the CD8 1 OT-I flow cytometry profiles represent a repeat experiment of our previously published data [13].Eur. J. Immunol.…”

“…Various mechanisms have been suggested to underlie such suppression, including induction of CD4 1 T-cell apoptosis [6][7][8], suppression of DC function [9][10][11][12], or the generation of suppressive cytokines [1]. The observed humoral and cell-mediated immunity to malaria is, however, hard to reconcile with evidence of immune suppression, but may be explained by the ability of suppressive mechanisms to reduce but not completely prevent induction of immunity.Recently, we provided evidence that blood-stage Plasmodium berghei infection leads to suppression of MHC class I (MHC I)-restricted immune responses as a consequence of apparently normal DC activation [13]. While DC in infected mice were …”

Comment le virus de l’hépatite C détourne la réponse immunitaire adaptative orchestrée par les cellules dendritiques

“…: TNF-), s'est avérée être un prérequis incontournable in vivo pour qu'il y ait induction d'effecteurs mémoire T fonctionnels [28,32]. On sait maintenant que l'activation indirecte des CDM qui n'ont pas encore rencontré l'agent pathogène (donc ni PAMP, ni antigènes) a pour conséquence de limiter leur participation à la présentation d'antigènes, principalement en arrêtant la capture des antigènes exogènes par phagocytose et en empêchant la formation de nouveaux complexes CMH-II-peptide [33,34]. En extrapolant à partir des travaux préalablement cités, on peut considérer que le nombre de CDM qui répondent à un pathogène donné est probablement petit si l'on considère que toutes les CDM qui présenteront aux lymphocytes T des antigènes d'une spécificité donnée devront d'abord avoir été en contact direct avec les composants dudit pathogène.…”