B7/CD28-Dependent CD4+CD25+ Regulatory T Cells Are Essential Components of the Memory-Protective Immunity to Candida albicans

Abstract

Protective immunity to the fungus Candida albicans is mediated by Ag-specific Th1 cells. Paradoxically, some Th2 cytokines are required for the maintenance of Th1-mediated immune resistance to the fungus. Therefore, in addition to the Th1/Th2 balance, other mechanisms seem to be involved in the regulation of Th1 immunity to the fungus. Here we show that CD4+CD25+ T cells, negatively regulating antifungal Th1 reactivity, are generated in mice with candidiasis. CD4+CD25+ T cells were not generated in B7-2- or CD28-deficient mice or in condition of IL-10 signaling deficiency. Accordingly, although capable of efficiently restricting the fungal growth, these mice experienced inflammatory pathology and were incapable of resistance to reinfection. CD4+CD25+ T cells poorly proliferated in vitro; were highly enriched for cells producing IL-4, IL-10, and TGF-β; and required IL-10-producing, Candida hypha-activated dendritic cells for generation. Adoptive transfer of CD4+CD25+ T cells or IL-10-producing dendritic cells restored resistance to reinfection and decreased inflammation in B7-2-deficient mice. These results show that oral tolerance induced by Candida hyphae is required for the occurrence of long-lasting protective immunity after yeast priming. The implication is that preventing reactivation rather than favoring sterilizing immunity to ubiquitous fungal pathogens may represent the ultimate expectation of vaccine-based strategies.

The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo

“…The interesting finding was that IL-10 production was greatly reduced in DCs from these mice in response to fungi. Because IL-10-producing DCs are required for the expression of long-lasting memory antifungal immunity through the induction of regulatory T cells (58), it is possible that the Th1 hyporesponsiveness of TLR2-deficient mice is a consequence of the decreased IL-10 production by DCs. Whatever the mechanism is, our finding is consistent with the defective response to vaccination with Borrelia burgdorferi OspA seen in TLR2-deficient mice (36) as well as with the TLR2 dependency of IL-10 production in response to Aspergillus hyphae (27) .…”

IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance

“…The origin and characteristics of the C. albicans strain used in this study have already been described [38]. For gastrointestinal infection, 10 8 Candida cells were injected intragastrically, and quantification of fungal growth was expressed as CFU per organ (mean AE SE) as described [38].…”

“…For gastrointestinal infection, 10 8 Candida cells were injected intragastrically, and quantification of fungal growth was expressed as CFU per organ (mean AE SE) as described [38]. For the i.v.…”

“…Pulsing of DC and culture of cells DC were exposed to live unopsonized fungi, with and without 10 ng/mL cytokines or neutralizing antibodies (10 lg/mL), at a 1 : 1 cell/fungus ratio, as described [38,39]. At 12 h of culture, cells were harvested for RT-PCR and supernatants were assessed for cytokine contents by ELISA.…”

“…Splenic CD4 + T cells (10 6 /mL) were cultured in flat-bottom 96-well plates in the presence of 5 Â 10 5 Candida-pulsed splenic DC for 5 days, before cytokine quantification in culture supernatants. Unfractionated MLN or TLN cells were cultured with inactivated fungi as described [38,39], before cytokine determination in culture supernatants 5 days later.…”