IFN-γ Receptor Signaling Regulates Memory CD8+ T Cell Differentiation

Sercan, Özen; Stoycheva, Diana; Hämmerling, Günter J.; Arnold, Bernd; Schüler, Thomas

doi:10.4049/jimmunol.0902708

Cited by 63 publications

(68 citation statements)

References 39 publications

(67 reference statements)

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“…We showed that IFN-gR-deficient (IFN-gR 2/2 ) and wild-type (WT) CD8 + TCR-tg OT-I T cells responding to their cognate peptide SIINFEKL did not differ with regard to CD62L expression, expansion, or T M formation (7). In contrast, the frequency of CD62L hi IFN-gR 2/2 OT-I T cells was strongly increased when both OT-I populations underwent LIP in Rag-deficient (Rag 2/2 ) mice (7).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we studied the impact of IFN-g on CD8 + T M generation and differentiation (7,16). We showed that IFN-gR-deficient (IFN-gR 2/2 ) and wild-type (WT) CD8 + TCR-tg OT-I T cells responding to their cognate peptide SIINFEKL did not differ with regard to CD62L expression, expansion, or T M formation (7).…”

Section: Resultsmentioning

confidence: 99%

“…+ T cell clones (5), others expand independently of IFN-g (6,7). This suggests that IFN-gR signaling in CD8 + T cells affects their expansion in a context-dependent fashion, probably determined by clone-specific features or the nature of the pathogen.…”

Section: F Unctional Plasticity Of Individual Cd8mentioning

confidence: 97%

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IFN-γ Regulates CD8+ Memory T Cell Differentiation and Survival in Response to Weak, but Not Strong, TCR Signals

Stoycheva

Deiser

Stärck

et al. 2015

The Journal of Immunology

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In response to primary Ag contact, naive mouse CD8+ T cells undergo clonal expansion and differentiate into effector T cells. After pathogen clearance, most effector T cells die, and only a small number of memory T cell precursors (TMPs) survive to form a pool of long-lived memory T cells (TMs). Although high- and low-affinity CD8+ T cell clones are recruited into the primary response, the TM pool consists mainly of high-affinity clones. It remains unclear whether the more efficient expansion of high-affinity clones and/or cell-intrinsic processes exclude low-affinity T cells from the TM pool. In this article, we show that the lack of IFN-γR signaling in CD8+ T cells promotes TM formation in response to weak, but not strong, TCR agonists. The IFN-γ–sensitive accumulation of TMs correlates with reduced mammalian target of rapamycin activation and the accumulation of long-lived CD62LhiBcl-2hiEomeshi TMPs. Reconstitution of mammalian target of rapamycin or IFN-γR signaling is sufficient to block this process. Hence, our data suggest that IFN-γR signaling actively blocks the formation of TMPs responding to weak TCR agonists, thereby promoting the accumulation of high-affinity T cells finally dominating the TM pool.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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IFN-γ Regulates CD8+ Memory T Cell Differentiation and Survival in Response to Weak, but Not Strong, TCR Signals

Stoycheva

Deiser

Stärck

et al. 2015

The Journal of Immunology

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“…However, we cannot exclude that Dex also blocked other, IFN-g-independent signaling pathways in IEC, which promoted IL-7 production. So far, we have no evidence for reduced T-cell numbers in secondary lymphoid organs of IFN-g À/À mice [25,26]. Hence, the lack of IFN-g-induced IL-7 production in the intestine of IFN-g À/À mice ( Fig.…”

Section: Il-7mentioning

confidence: 99%

Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

et al. 2010

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IL-7 is a major regulator of lymphocyte homeostasis; however, little is known about the mechanisms that regulate IL-7 production. To study Il7 gene regulation in vivo, we generated a novel IL-7-reporter mouse, which allows the non-invasive quantification of Il7 gene activity in live mice and, additionally, the simultaneous activation/inactivation of target genes in IL-7-producing cells. With these IL-7-reporter mice, we identify thymus, skin and intestine as major sources of IL-7 in vivo. Importantly, we show that IFN-c and the commensal microflora promote steady-state IL-7 production in the intestine. Furthermore, we demonstrate that the blockade of IFN-c signaling in intestinal epithelial cells strongly reduces their IFN-c-driven IL-7 production. In summary, our data suggest a feedback loop in which commensal bacteria drive IFN-c production by lymphocytes, which in turn promotes epithelial cell IL-7 production and the survival of IL-7-dependent lymphocytes.Key words: Commensal microflora . IFN-c . IL-7 . Intestinal epithelial cells Supporting Information available onlineIntroduction IL-7 is a central regulator of immune cell development and homeostasis. The tight regulation of IL-7 availability is crucial for host survival. For instance, the lack of IL-7 leads to severe immunodeficiency [1] while its overexpression causes aberrant T-cell activation [2] and autoimmunity [3][4][5].For a long time, it was believed that lymphoid tissues are the major sources of IL-7 in the body. IL-7 expression was detected in thymus, bone marrow and lymph nodes and it was assumed that IL-7 production is constant and largely unaffected by external stimuli [6,7]. However, recent reports challenged this view demonstrating that Il7 gene activity is differentially regulated in hepatocytes and lymphoid stroma cells [8,9]. Despite its central importance for host survival, the mechanisms regulating IL-7 production in vivo are largely unknown.A better understanding of these mechanisms is hampered by the fact that the visualization and isolation of IL-7-producing cells by immunohistochemistry is sometimes difficult to achieve [10,11]. To circumvent this problem and define the impact of IL-7-producing cells on immune regulation, we have generated a bacterial artificial chromosome (BAC)-transgenic IL-7 reporter mouse that allows the non-invasive visualization of Il7 gene expression in live mice via bioluminescent imaging and the Eur. J. Immunol. 2010. 40: 2391-2400 DOI 10.1002 HIGHLIGHTS 2391Frontline simultaneous, Cre-mediated manipulation of target genes in IL-7-producing cells. With the help of this novel IL-7 reporter mouse, we identify thymus, skin and intestine as major sources of IL-7 in the body. In the steady state, the commensal microflora and IFN-g promote Il7 gene activity in intestinal epithelial cells (IEC). This can be blocked by the anti-inflammatory drug dexamethasone (Dex), which directly interferes with IFN-g signaling in IEC. Since IL-7 promotes T-cell survival and function, our data suggest that commensal-driven IFN-g p...

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“…Id1, in turn, increase the expression of TNFα and IFNγ in the middle ear epithelial cells. These two inflammatory cytokines and mediators are deeply involved in the inflammatory and immune responses of the middle ear mucosa because they are linked to the activity of infiltrated T cells (so called CTLs or pathogen specific T cells) in the middle ear mucosa [54,55]. IFNγ and TNFα produced by infiltrated T cells affect the middle ear immunity via PD-L1 (Figure 2).…”

Section: Important Inflammatory Cytokines and Mediators In Ommentioning

confidence: 99%

Adaptive Immunity in the Middle Ear Mucosa with Chronic Otitis Media

Lin¹,

Zhao²

2014

Int J Otorhinolaryngol

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IFN-γ Receptor Signaling Regulates Memory CD8+ T Cell Differentiation

Abstract: Material Supplementary 8.DC1http://www.jimmunol.org/content/suppl/2010/02/15/jimmunol.090270

Cited by 63 publications

References 39 publications

IFN-γ Regulates CD8+ Memory T Cell Differentiation and Survival in Response to Weak, but Not Strong, TCR Signals

IFN-γ Regulates CD8+ Memory T Cell Differentiation and Survival in Response to Weak, but Not Strong, TCR Signals

Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

Adaptive Immunity in the Middle Ear Mucosa with Chronic Otitis Media

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