Cutting Edge: Early IL-4 Production Governs the Requirement for IL-27-WSX-1 Signaling in the Development of Protective Th1 Cytokine Responses following <i>Leishmania major</i> Infection

Artis, David; Johnson, Leanne M.; Joyce, Karen L.; Saris, Christiaan J. M.; Villarino, Alejandro V.; Hunter, Christopher A.; Scott, Phillip

doi:10.4049/jimmunol.172.8.4672

Cited by 92 publications

(128 citation statements)

References 18 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…4B). These findings demonstrated that early IFN-␥ production is intact in WSX-1 Ϫ/Ϫ mice infected with T. muris, and are consistent with recent reports that have identified WSX-1-independent Th1 responses in vivo (11,15,17).…”

Section: Enhanced Production Of Th2 Cytokines and Rapid Expulsion Of supporting

confidence: 81%

“…For instance, following infection with L. major, which is characterized by the development of a mixed Th1/Th2 cytokine response, WSX-1 expression is required to promote optimal IFN-␥ production, most likely via STAT1-mediated induction of T-bet (10). However, blockade of IL-4 extinguishes the requirement for WSX-1 in promoting Th1 cell differentiation and immunity to L. major, demonstrating that the requirement for WSX-1 in type 1 immunity is restricted to a nonpolarized cytokine environment (11). Consistent with this proposed pathway, previous studies have shown that STAT1-dependent Th1 cell development is regulated by the presence of IL-4 (32).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously demonstrated that in a nonpolarized cytokine milieu, IL-27/ WSX-1 signaling can promote IFN-␥ production and type 1-mediated immunity (4,5,11,15,31). For instance, following infection with L. major, which is characterized by the development of a mixed Th1/Th2 cytokine response, WSX-1 expression is required to promote optimal IFN-␥ production, most likely via STAT1-mediated induction of T-bet (10).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, while the IL-12R plays a critical role in the expansion of Th1 cells (9), it has been reported that WSX-1-deficient T cells express lower levels of T-bet and IFN-␥ (4,5,10). Furthermore, we recently demonstrated that in a nonpolarized cytokine environment that develops following exposure to Leishmania major infection, WSX-1 is critical in promoting the development of Th1 cells (11). As a consequence of these studies, a consensus has emerged that IL-27/WSX-1 is an important pathway for the generation of optimal type 1 responses (1,(12)(13)(14).…”

mentioning

confidence: 99%

See 3 more Smart Citations

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Artis¹,

Villarino²,

Silverman

et al. 2004

The Journal of Immunology

Self Cite

222

210

View full text Add to dashboard Cite

Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1−/− mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4+ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.

show abstract

Section: Enhanced Production Of Th2 Cytokines and Rapid Expulsion Of supporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Artis¹,

Villarino²,

Silverman

et al. 2004

The Journal of Immunology

Self Cite

222

210

View full text Add to dashboard Cite

show abstract

“…Again, a decreased resistance of WSX-1-KO mice to infection with L. major was accompanied by a normal IFN-␥ response, whereas the expression of IL-4 was elevated 6 wk after infection (26). Neutralization of IL-4 abolished the requirement for WSX-1 to promote early IFN-␥ production and control of L. major (47), suggesting that WSX-1 signaling is dispensable for Th1 T cell differentiation in the absence of IL-4. In contrast to L. major infection, resolving infection with gastrointestinal nematodes is dependent on the genetically determined expression of IL-4 and IL-13 (48).…”

Section: Discussionmentioning

confidence: 93%

The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis

Hölscher

Rückerl

et al. 2005

The Journal of Immunology

Self Cite

251

305

View full text Add to dashboard Cite

IL-12 is a potent inducer of IFN-γ production and promotes a protective cell-mediated immune response after Mycobacterium tuberculosis infection. Recently, the IL-12-related cytokine IL-27 was discovered, and WSX-1 was identified as one component of the IL-27R complex. To determine the functional significance of IL-27/WSX-1 during tuberculosis, we analyzed the course of infection and the immune response in WSX-1-KO mice after aerosol infection with M. tuberculosis. In the absence of WSX-1, an increased production of the proinflammatory cytokines TNF and IL-12p40 resulted in elevated CD4+ T cell activation and IFN-γ production, which enhanced macrophage effector functions and reduced bacterial loads. This is the first occasion of a selectively gene-deficient mouse strain showing higher levels of protective immunity against M. tuberculosis infection than wild-type mice. However, a concomitantly increased chronic inflammatory response also accelerated death of infected WSX-1-KO mice. In vitro, IL-27 induced STAT3 phosphorylation and inhibited TNF and IL-12 production in activated peritoneal macrophages, indicating a novel feedback mechanism by which IL-27 can modulate excessive inflammation. In conclusion, IL-27 both prevents optimal antimycobacterial protection and limits the pathological sequelae of chronic inflammation.

show abstract

Impaired Th1 responses in mice deficient in Epstein‐Barr virus‐induced gene 3 and challenged with physiological doses of Leishmania major

et al. 2005

View full text Add to dashboard Cite

Protection against Leishmania major is dependent on IL‐12 release from L. major‐infected dendritic cells (DC) that induce IFN‐γ‐producing Th1/Tc1 cells. IL‐27, a novel member of the IL‐12 family, is a heterodimer composed of p28 and IL‐12p40‐related Epstein‐Barr virus‐induced gene 3 (EBI3), and was shown to be produced by DC. In this study, we utilized EBI3‐deficient mice to investigate the role of IL‐27 in leishmaniasis using physiological low‐dose infections that mimic natural transmissions. Lesions in EBI3–/– mice were significantly larger between weeks 3 and 10 post infection, reaching up to approximately threefold increased lesion volumes compared to wild types. In parallel, dermal lesions of EBI3–/– mice contained greater parasite numbers, reaching a peak load that was 2‐log higher than in C57BL/6 mice. However, lesions in EBI3–/– and wild‐type mice resolved after 12 weeks. At early time points, the antigen‐specific cytokine response in EBI3–/– lymph nodes showed increased levels of IL‐4, IL‐10 and IL‐13 and decreased IFN‐γ production. IL‐27 production was restricted to the DC population, since the majority of EBI3 expression in lymph nodes of infected mice was found in CD11c+ cells. In conclusion, our data show that DC‐derived IL‐27 is critical for the timely initiation of efficient anti‐parasite Th1 immunity early in infections.

show abstract

Cutting Edge: Early IL-4 Production Governs the Requirement for IL-27-WSX-1 Signaling in the Development of Protective Th1 Cytokine Responses following Leishmania major Infection

Cited by 92 publications

References 18 publications

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis

Impaired Th1 responses in mice deficient in Epstein‐Barr virus‐induced gene 3 and challenged with physiological doses of Leishmania major

Contact Info

Product

Resources

About