Icsbp1/IRF-8 Is Required for Innate and Adaptive Immune Responses against Intracellular Pathogens

Abstract

The chronic myeloid leukemia syndrome of the BXH-2 mouse strain (Mus musculus) is caused by a recessive mutation (R294C) in the transcriptional regulator Icsbp1/IRF-8. In trans activation assays using an IL-12p40 gene reporter construct introduced in RAW 264.7 mouse macrophages, we show that the Icsbp1C294 isoform behaves as a partial loss-of-function. The Icsbp1C294 hypomorph allele appears to have a threshold effect on IL-12 production, with pleiotropic consequences on resistance to different types of infections in vivo. Despite the presence of a resistance Nramp1G169 allele, BXH-2 mice (Icsbp1C294) show impaired control of Mycobacterium bovis (bacille Calmette-Guérin) multiplication both early and late during infection, with uncontrolled replication linked to inability to form granulomas in infected liver and spleen. Studies in informative (BXH-2 × BALB/cJ)F2 mice show that homozygosity for Icsbp1C294 causes susceptibility to Salmonella enterica serovar Typhimurium to a level comparable to that seen for mice lacking functional Nramp1 or TLR4. Finally, impaired Icsbp1C294 function is associated with the following: 1) increased replication of the Plasmodium chabaudi AS malarial parasite during the first burst of blood parasitemia, and 2) recurring waves of high blood parasitemia late during infection. These results show that Icsbp1 is required for orchestrating early innate responses and also long-term immune protection against unrelated intracellular pathogens.

Inhibition of ERK MAPK Suppresses IL-23- and IL-1-Driven IL-17 Production and Attenuates Autoimmune Disease

“…It has previously been reported that MyD88-mediated activation of NF-B, IRF1, and IRF8 are required for IL-12p35 and IL12p40 gene expression and driving Th1 responses (17)(18)(19)(20). However, these studies failed to find a role for these transcriptional factors in IL-23-driven Th17 responses and suggested that alternative signaling molecules may be involved (18,20).…”

“…However, the induction of IL-12 and IL-23 are differentially regulated by TLR and NOD-like receptor-activated DC (7). NF-B, IFN regulatory factor (IRF)1, and IRF8 signaling pathways play important roles in the expression of IL12p35 and IL-12p40 and in driving Th1 responses (17)(18)(19)(20). In contrast, it has been demonstrated that IL-6 and IL-23 production in DC by agonists of dectin-1, and consequent development of Th17 cells, is mediated by signaling via Syk and CARD9 (21).…”

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

“…However, IL-21 KO mice are unable to control P. chabaudi parasitemia (88). Not surprisingly, the absence of CD8 + DC in this infection results in impaired parasite control and more pronounced relapses (40).…”

“…Another study analyzing CD4 + T cell responses to P. chabaudi Ag showed CD8 + DC as superior to CD8 2 DC at MHC II presentation in the steady-state, but the latter were more efficient during infection (39). In the P. chabaudi model, mice devoid of CD8 + DC developed higher peaks of parasitemia and more pronounced relapses than did their WT counterparts (40). These results suggested an important role for CD8 + DC in the development of T cell responses against blood-stage malaria parasites.…”

Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9

“…43,44 Similarly, mice carrying a mutation in IRF-8 (BXH-2) are extremely susceptible to P. chabaudi. 45 Therefore, uncontrolled early parasite replication in the AcB62 strain could be linked to an impaired early inflammatory response and/or dampened polarization of the critical, early Th1 response. 46 The minimal Char10 region is large, B20 Mb; numerous genes associated with the innate or protective immune response map within Char10.…”