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

Abstract

Despite extensive evidence that Plasmodium species are capable of stimulating the immune system, the association of malaria with a higher incidence of other infectious diseases and reduced responses to vaccination against unrelated pathogens suggests the existence of immune suppression. Recently, we provided evidence that blood-stage Plasmodium berghei infection leads to suppression of MHC class I-restricted immunity to third party (non-malarial) antigens as a consequence of systemic DC activation. This earlier study did not, however, determine whether reactivity was also impaired to MHC class II-restricted third party antigens or to Plasmodium antigens themselves. Here, we show that while P. berghei-expressed antigens were presented early in infection, there was a rapid decline in presentation within 4 days, paralleling impairment in MHC class I-and II-restricted presentation of third party antigens. This provides important evidence that P. berghei not only causes immunosuppression to subsequently encountered third party antigens, but also rapidly limits the capacity to generate effective parasite-specific immunity.Key words: Antigen presentation . DC . Parasitic-Protozoan . Rodent . T cells IntroductionDespite extensive evidence that Plasmodium species are capable of stimulating the immune system, numerous studies have described immune suppression associated with infection, suggesting that Plasmodium parasites subvert immunity to promote persistence [1][2][3][4][5]. 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 1674shown to be fully competent in their ability to cross-present cellular antigens to CD8 1 T cells, provided they expressed antigen-MHC complexes on the surface, their activation phenotype led to a failure to capture newly encountered antigenic material and thus a failure to present such antigens [13]. In this case, DC were not directly suppressed but merely followed their normal maturation pathway after encounter with activatory stimuli. The net effect, however, was one of rapid, generalised immunosuppression because as the systemic infection progressed, all DC became activated, leaving no immature DC to capture subsequently encountered antigens.While systemic DC activation by P. berghei explained the reduced reactivity to subsequently encountered third party (nonmalarial) MHC I-restricted antigens, this earlier study did not determine whether reactivity...

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…Although the use of these parasites in conjunction with model T cell lines has aided the study of antimalarial CD4 + and CD8 + T cell responses (6,(11)(12)(13)(14)(15), wild-type (WT) parasites and transgenic T cells capable of recognizing authentic parasitederived Ags are preferred, as they more closely resemble endogenous responses to natural infections. With this in mind, we recently generated a murine TCR transgenic line of PbA-specific CD8 + T cells, termed PbT-I (8,16).…”

Prevention of Experimental Cerebral Malaria by Flt3 Ligand during Infection with Plasmodium berghei ANKA

“…DCs can phagocytose malaria-parasitized red blood cells during infection and can present malaria antigen in both the major histocompatibility complex (MHC) class I and class II pathways, activating malaria-specific CD8 ϩ and CD4 ϩ T cells, respectively, and thus playing critical roles in the induction of protective immunity against Plasmodium infection (15,17,19,20,25,33). However, DCs also play an important role in the pathogenesis of ECM, a T cell-dependent disease.…”

The Subcellular Location of Ovalbumin in Plasmodium berghei Blood Stages Influences the Magnitude of T-Cell Responses

“…Transgenic Plasmodium parasites expressing ovalbumin (OVA) in the cytoplasm have been used successfully to examine parasitespecific CD8 ϩ responses during both blood and liver stages of infection (5)(6)(7). These parasites do not, however, induce strong OVA-specific CD4 ϩ T-cell responses in vivo (8). One potential explanation for the dichotomy in the ability of these parasites to prime OVA-specific CD4 ϩ T-cell and OVA-specific CD8 ϩ T-cell responses is that different antigen-processing and -presenting pathways exist for the presentation of antigens by major histocompatibility complex (MHC) class I and MHC class II molecules (9) and that OVA expressed from the cytoplasmic location does not effectively enter the MHC class II antigen-processing pathway.…”