Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity

Abstract

Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4 + Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ-producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8 -cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8 -splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN-inducing pathogens.

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…In murine models of Plasmodium in which death is associated with immunopathology, such as P. berghei, the absence of IFNAR leads to reduced tissue pathology and reduced mortality (24,(67)(68)(69). Treatment with IFN-α or IFN-β, both prior to and during infection, however, reduces lethality, implying a role for early parasite control in contributing to lethality (70,71).…”

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”

Host-mediated impairment of parasite maturation during blood-stage Plasmodium infection

“…Given that the reduced parasite maturation rate was observed only a few days into the infection, we next investigated a possible role for host inflammatory responses in mediating this phenomenon (14). To begin exploring this, we first blocked type-I IFN cytokine signaling via the receptor IFNAR1, because our previous data had suggested this innate immune signaling pathway could influence circulating pRBC numbers and life stages in vivo (24) (Fig. 2C).…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Importantly, Ab blockade of type I IFNR prevents disease progression and the death of infected mice. Together, these findings reveal that type I IFNs regulate parasite control by suppressing IFN-g production and suggest that blockade of type I IFN signaling during severe malaria infection may provide a novel adjunct therapy (168).…”

“…Interestingly, the enhanced resistance is associated with increased numbers of IFN-g-secreting CD4 + T cells (167). In a follow-up study, type I IFNs were shown to act directly on splenic conventional dendritic cells to impair their ability to phagocytose parasites and prime Th1 cells (168). In addition, deficiency in type I IFN signaling results in an increase in MHC class II expression.…”