Functional yet Balanced Reactivity to Candida albicans Requires TRIF, MyD88, and IDO-Dependent Inhibition of Rorc

Abstract

The ability of regulatory T (Treg) cells to inhibit aspects of innate and adaptive immunity is central to their protective function in fungal infections. In murine candidiasis, CD4+CD25+ Treg cells prevent excessive inflammation but enable fungal persistence in the gastrointestinal tract, which underlies the onset of durable antifungal protection. In this study, we show that fungal growth, inflammatory immunity, and tolerance to the fungus were all controlled by the coordinate activation of naturally occurring Treg cells, which limited early inflammation at the sites of infection, and pathogen-induced Treg cells (that regulated the expression of adaptive Th immunity in secondary lymphoid organs). Naturally occurring Treg cells required the TRIF pathway for migration to inflamed sites, where the MyD88 pathway would then restrain their suppressive function. Subsequent inflammatory Th1-type immunity was modulated by induced Treg cells, which required the TRIF pathway as well, and acted through activation of IDO in dendritic cells and Th17 cell antagonism. In vitro, using naive CD4+ cells from TRIF-deficient mice, tryptophan metabolites were capable of inducing the Foxp3-encoding gene transcriptionally and suppressing the gene encoding RORγt, Th17 lineage specification factor. This is the first study to show that the same tryptophan catabolites can foster dendritic cell-supported generation of Foxp3+ cells and mediate, at the same time, inhibition of RORγt-expressing T cells.

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…Alternatively, it is possible that IDO plays a role in blocking the generation of Th1 and Th17 cells. Such a role has been shown for tryptophan metabolites in the generation of IL-17-producing CD4ϩ and ␥␦ T cells in models of fungal infection (29,43). Finally, a combination of both mechanisms, i.e., reduced Th1 cell death and increased Th17 differentiation, can account for the observed results in the absence of IDO.…”

The contribution of PARs to inflammation and immunity to fungi

“…Interestingly, both treatments oppositely affected parameters of adaptive immunity to the fungus, such as the interleukin ARTICLES (IL)-12 / IL-10 production by Peyer ' s patch dendritic cells, known to be regulated by PAR signaling, 8 and the pattern of ifn or il10 gene expression in CD4 + T cells from mesenteric lymph nodes of WT mice. PAR 1 -AP promoted the IL-12 / Th1 response and PAR 1 -ANT promoted the IL-10 + T regulatory cell response 35 to the fungus ( Figure 5c ). Thus, the upregulated expression of PAR 1 in candidiasis correlates with the occurrence of local and adaptive inflammatory responses.…”

“…Total RNA from organs or purified CD4 + T cells 35 was extracted with TRIZOL (Invitrogen SRL Life Technologies, Milano, Italy). Synthesis and PCR of cDNA were performed as described.…”

“…12,34 The forward and reverse PCR primers used for murine and human par and gapdh and cycles ARTICLES were as described. 12,34,35 Semiquantitative PCR was performed using the " primer-dropping " method, in which gapdh was coamplified as an internal control in all reactions. Band intensity was quantified using laser scanning densitometry and ratios of par1 or par2 to gapdh were plotted for each autoradiogram.…”

Mice Deficient in MyD88 Develop a Th2-Dominant Response and Severe Pathology in the Upper Genital Tract following Chlamydia muridarum Infection

“…Although both MyD88-and TRIF-mediated signaling pathways are required for optimal detection of microbial infection (19,20), different pathways may be preferred for dealing with different infections. Activation of TRIF-dependent pathways can lead to increased production of antiviral molecules (21), whereas activation of MyD88-dependent pathways can result in a wide spectrum of antimicrobial responses.…”