Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-γ– and Tumor Necrosis Factor (TNF)-α–dependent Host Resistance to the Intracellular Pathogen, <i>Toxoplasma gondii </i>

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118

142

IFN-γ-producing CD8+ T lymphocytes are essential effector cells that mediate protective immunity during murine toxoplasmosis, and yet their effector development remains poorly characterized. Vaccination with the carbamoyl phosphate synthase (CPS) mutant strain of Toxoplasma gondii was used to examine the CD8+ T cell response in the peritoneal effector site. Four CTL subpopulations with varying effector potentials were defined based on the expression of effector molecules and the cell surface activation markers CD62L and killer cell lectin-like receptor G1 (KLRG1). Further phenotypic analysis revealed that the acquisition of KLRG1 among effector subpopulations correlated with the down-regulation of both IL-7R and CD27, suggesting that KLRG1 marks dominant, end-stage effector cells. Using gene-targeted mice, we tested the in vivo requirements of key IL-12 signaling components for effector CTL differentiation. Contrary to established models of viral and bacterial infection, CD8+ T cell-intrinsic IL-12 signaling was required for the generation of IFN-γ-producing CTLs in response to T. gondii. Importantly, the development of the KLRG1+ effector subpopulations, but not the memory precursor-containing KLRG1− effector subset, was critically reliant on IL-12. Furthermore, IL-12 signaling-dependent T-bet expression was also found to be important for differentiation of KLRG1+ effectors. Our results underscore a vital role for IL-12 in not only the induction of IFN-γ expression but also in the development of heterogeneous subpopulations of effector CD8+ T cells generated in response to the intracellular parasite T. gondii.

Section: Il-12 Signaling Drives Cd8 ؉ T Cell Ifn-␥ Production and Difmentioning

confidence: 99%

“…Spleens were also harvested for select experiments. Single cell suspensions of tissues were washed and erythrocytes were lysed using a Tris-buffered NH 4 Cl solution. Live cell numbers were counted on a hemocytometer using trypan blue exclusion.…”

Section: Tissue Preparation and In Vitro Restimulationmentioning

confidence: 99%

IL-12 Signaling Drives CD8+ T Cell IFN-γ Production and Differentiation of KLRG1+ Effector Subpopulations during Toxoplasma gondii Infection

Wilson

Matthews

Yap

2008

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142

“…The immune response to T. gondii is characterized by the induction of a vigorous Th1 cell-mediated response, and high levels of IFN-␥ are necessary for control of both acute and chronic stages of infection in the murine system (12,13). IL-12 is required for resistance to acute and chronic toxoplasmosis due to its essential role in stimulating production of IFN-␥ (14,15).…”

Section: Production Of Il-12 By Macrophages Infected Withmentioning

confidence: 99%

Production of IL-12 by Macrophages Infected withToxoplasma gondiiDepends on the Parasite Genotype

Robben¹,

Mordue²,

Truscott

et al. 2004

182

169

Three clonal strain types (I, II, and III) of Toxoplasma gondii predominate worldwide. The outcome of infection in mice is highly dependent on the parasite genotype with type I strains being uniformly virulent, while types II and III are nonvirulent. Interactions with the innate immune response play a major role in determining the outcome of infection in the murine model. To identify key early differences in the innate immune response that contribute to pathogenesis, we examined the cytokine production of macrophages after in vitro infection with parasites of virulent type I and nonvirulent type II genotypes. Infection with type II strain parasites stimulated the production of proinflammatory cytokines, and particularly high levels of the Th1-polarizing cytokine, IL-12. Infection with type II strain parasites stimulated NF-κB nuclear translocation at early time points and led to the up-regulation of mRNA levels of IL-12 and other proinflammatory cytokines that was dependent on the myeloid differentiation factor 88 signaling pathway. Induction of IL-12 required active invasion by live parasites and was not blocked by infection with virulent type I strain parasites, arguing against an active inhibition of signaling. Our findings suggest that early induction of high levels of IL-12 by macrophages infected with type II strain parasites may contribute to more effective control.

“…(1)(2)(3)(4). IFN-g is a potent proinflammatory cytokine derived from multiple cells of both the innate and adaptive immune system, including CD4 + Th1 cells, CD8 + T cells, and NK cells.…”

mentioning

confidence: 99%

IL-22 Mediates Host Defense against an Intestinal Intracellular Parasite in the Absence of IFN-γ at the Cost of Th17-Driven Immunopathology

Stange

Hepworth

Rausch

et al. 2012

The roles of Th1 and Th17 responses as mediators of host protection and pathology in the intestine are the subjects of intense research. In this study, we investigated a model of intestinal inflammation driven by the intracellular apicomplexan parasite Eimeria falciformis. Although IFN-γ was the predominant cytokine during E. falciformis infection in wild-type mice, it was found to be dispensable for host defense and the development of intestinal inflammation. E. falciformis-infected IFN-γR−/− and IFN-γ−/− mice developed dramatically exacerbated body weight loss and intestinal pathology, but they surprisingly harbored fewer parasites. This was associated with a striking increase in parasite-specific IL-17A and IL-22 production in the mesenteric lymph nodes and intestine. CD4+ T cells were found to be the source of IL-17A and IL-22, which drove the recruitment of neutrophils and increased tissue expression of anti-microbial peptides (RegIIIβ, RegIIIγ) and matrix metalloproteinase 9. Concurrent neutralization of IL-17A and IL-22 in E. falciformis-infected IFN-γR−/− mice resulted in a reduction in infection-induced body weight loss and inflammation and significantly increased parasite shedding. In contrast, neutralization of IL-22 alone was sufficient to increase parasite burden, but it had no effect on body weight loss. Treatment of an E. falciformis-infected intestinal epithelial cell line with IFN-γ, IL-17A, or IL-22 significantly reduced parasite development in vitro. Taken together, to our knowledge these data demonstrate for the first time an antiparasite effect of IL-22 during an intestinal infection, and they suggest that IL-17A and IL-22 have redundant roles in driving intestinal pathology in the absence of IFN-γ signaling.