The Cytokines Interleukin 27 and Interferon-γ Promote Distinct Treg Cell Populations Required to Limit Infection-Induced Pathology

Hall, Aisling O’Hara; Beiting, Daniel; Tato, Cristina M.; John, Beena; Oldenhove, Guillaume; Lombana, Cláudia; Pritchard, Gretchen Harms; Silver, Jonathan Js; Bouladoux, Nicolas; Stumhofer, Jason Js; Harris, Tajie H.; Grainger, John; Wojno, Elia Tait; Wagage, Sagie; Roos, David S.; Scott, Philip P; Turka, Laurence La; Cherry, Sara; Reiner, Steven; Daniel, Dylan; Belkaid, Yasmine; Elloso, M. Merle; Hunter, Christopher A.

doi:10.1016/j.immuni.2012.06.014

Cited by 310 publications

(368 citation statements)

References 53 publications

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“…These data were in apparent contrast to previous reports where IL-27 deficiency in vivo more often led to an elevation in the magnitude of T-cell response (13,15,22,30). However, these published data monitored T-cell responses during infectious challenge, raising the possibility that the IL-27 dependence might be unique to the cellular response elicited by subunit vaccination.…”

Section: Resultscontrasting

confidence: 86%

See 1 more Smart Citation

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Pennock

Gapin

Kedl

2014

Proc. Natl. Acad. Sci. U.S.A.

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An elusive goal of cellular immune vaccines is the generation of large numbers of antigen-specific T cells in response to subunit immunization. A broad spectrum of cytokines and cell-surface costimulatory molecules are known to shape the programming, magnitude, and repertoire of T cells responding to vaccination. We show here that the majority of innate immune receptor agonistbased vaccine adjuvants unexpectedly depend on IL-27 for eliciting CD4 + and CD8 + T-cell responses. This is in sharp contrast to infectious challenge, which generates T-cell responses that are IL-27-independent. Mixed bone marrow chimera experiments demonstrate that IL-27 dependency is T cell-intrinsic, requiring T-cell expression of IL-27Rα. Further, we show that IL-27 dependency not only dictates the magnitude of vaccine-elicited T-cell responses but also is critical for the programming and persistence of high-affinity T cells to subunit immunization. Collectively, our data highlight the unexpected central importance of IL-27 in the generation of robust, high-affinity cellular immune responses to subunit immunization.

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Section: Resultscontrasting

confidence: 86%

“…Additionally, IL-27 displays different effects on CD4 + and CD8 + T-cell responses, enhancing tumor-specific CD8 + T-cell responses (17)(18)(19) while also inducing IL-10-producing CD4 + T cells (13,20,21) and Tregs (22).…”

mentioning

confidence: 99%

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Pennock

Gapin

Kedl

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…We found that IFN-γ significantly increased in purified CD4 + T cells from HBV-carrier mice, similar to IL-10. Although IFN-γ is typically considered to be an antiviral cytokine, it also plays an important role in maintaining immune tolerance in other studies, where IFN-γ may be related to antigen-specific regulatory cell differentiation, development, or clonal deletion (30,31). The underlying mechanism for the role of IFN-γ, likely different from IL-10, remains elusive at present and needs further investigation in our model.…”

Section: Discussionmentioning

confidence: 98%

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The liver plays a critical role in inducing systemic immune tolerance, for example, during limiting hypersensitivity to food allergy and in rendering acceptance of allotransplant or even hepatotropic pathogens. We investigated the unknown mechanisms of liver tolerance by using an established hepatitis B virus (HBV)-carrier mouse model, and found that these mice exhibited an antigen-specific tolerance toward peripheral HBsAg vaccination, showing unenlarged draining lymph node (DLN), lower number of germinal centers (GC), and inactivation of GC B cells and follicular T helper (Tfh) cells. Both in vivo and in vitro immune responses toward HBsAg were suppressed by mononuclear cells from HBV-carrier mice, which were CD4 + Foxp3 − type 1 regulatory T (Tr1)-like cells producing IL-10. Using recipient Rag1 −/− mice, hepatic Tr1-like cells from day 7 of HBV-persistent mice acquired the ability to inhibit anti-HBV immunity 3 d earlier than splenic Tr1-like cells, implying that hepatic Tr1-like cells were generated before those in spleen. Kupffer cell depletion or IL-10 deficiency led to impairment of Tr1-like cell generation, along with breaking HBV persistence. The purified EGFP + CD4 + T cells (containing Tr1-like cells) from HBV-carrier mice trafficked in higher numbers to DLN in recipient mice after HBsAg vaccination, and subsequently inactivated both Tfh cells and GC B cells via secreting IL-10, resulting in impaired GC formation and anti-HB antibody production. Thus, our results indicate Tr1-like cells migrate from the liver to the DLN and inhibit peripheral anti-HBV immunity by negatively regulating GC B cells and Tfh cells.peripheral tolerance | unresponsive

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“…Consecutive studies imply that the activation of T-bet and the expression of CXCR3 in Tregs depend on IFNg and IL-27 signaling. 22,23 However, it remains unclear whether T-bet activation allows Tregs to acquire specific trafficking properties (for example, by CXCR3 expression) or strengthen certain Treg suppression capacities targeted to the corresponding T H 1 response. 1 Our data show that CXCR3 is crucial for the migration of Tregs into sites of inflammation and thereby, helps to control an excessive T H 1 response in crescentic GN.…”

Section: Discussionmentioning

confidence: 99%

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

Paust¹,

Riedel²,

Krebs³

et al. 2015

JASN

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Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the T H 1-associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA-associated crescentic GN and colocalize with CXCR3 + effector T cells.

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The Cytokines Interleukin 27 and Interferon-γ Promote Distinct Treg Cell Populations Required to Limit Infection-Induced Pathology

Cited by 310 publications

References 53 publications

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

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