Interleukin 10–Mediated Immunosuppression by a Variant CD4 T Cell Epitope of Plasmodium falciparum

Abstract

The immunodominant CD4 T cell epitope region, Th2R, of the circumsporozoite protein of Plasmodium falciparum is highly polymorphic. Such variation might be utilized by the parasite to escape from or interfere with CD4 T cell effector functions. Here, we show that costimulation with naturally occurring altered peptide ligands (APL) can induce a rapid change from IFNgamma production to the immunosuppressive mediator interleukin 10 (IL-10). This mechanism may contribute to the low levels of T cell responses observed to this pathogen in malaria-endemic areas.

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

“…By contrast, IL-10 might limit inflammation in the vicinity of spz invasion. IL-10 inhibits some T cell responses to P. falciparum Ag [31], but IL-10 also accompanies protective immunity in malaria endemic areas [32]. Hence, it is possible that the inflammatory and regulatory cytokines are coordinately induced during protection against malaria.…”

Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen

“…1 Evidence for its immunosuppressive activity has been based on the observations that (i) increased production of IL-10 ex vivo and in animal models was associated with states of immunosuppression, 2,3 (ii) neutralizing antibodies to IL-10 reversed hyporesponsiveness of T cells ex vivo, 4,5 and (iii) deletion of the IL-10 gene rendered mice more resistant to tumors or infection and more susceptible to infection pathology or autoimmune disease. [6][7][8][9] Substantial interindividual variability has been noted in several studies with humans, and heritability of high or low IL-10 secretion was observed.…”

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

“…Out of these peptides pairs only one pair (M5/M6) reflected the MAD20 allelic prevalence with reactivity of 65% and 35% in Gambian donors, respectively [16]. Reactivity to M3/M4 was equally distributed amongst donors, while [20,21]. Index peptide was pre-pulsed first at 30 lg/mL onto PBMC and the other variant 1 h later at the peptide concentrations indicated (10-90 lg/mL).…”

“…One possible explanation for the unexpected allelic T cell reactivity pattern to M3/4 and M7/8 was that some of the reactivity to these epitopes was being suppressed. In pre-erythrocytic malaria, CS protein variants can turn off some types of T cell responses to each other by APL antagonism and through immune interference with the stimulation of T cell responses in PBMC cultures [10,20,21]. We thus investigated whether a similar mechanism is involved in the case of allelic MSP-1 variants in malaria-exposed donors.…”

“…Proliferation to M3 or M4 was induced from PBMC by mixing peptide pre-pulsed (50 lg/mL) irradiated presenters with untreated PBMC used as responders at a ratio of 1:4. The influence of the presence of the variant on the proliferative response of the index peptide was assessed in a proliferative immune interference assay [20,21]. The index peptide and variant peptide were pre-pulsed (50 lg/mL) separately on irradiated autologous PBMC in separate Falcon tubes, washed and then mixed together at a 1:1 ratio with untreated PBMC or with each other.…”