T cells use two directionally distinct pathways for cytokine secretion

Huse, Morgan; Lillemeier, Björn F.; Kuhns, Michael S.; Chen, Daniel S.; Davis, Mark M.

doi:10.1038/ni1304

Cited by 399 publications

(460 citation statements)

References 52 publications

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“…A similar distribution has been reported for TNF-α in human breast cancer tissues [9]. For such distribution of immunoreactive proteins, computerized image analysis is far more reproducible than manual scoring in assessing positive areas [19,27]. Even so, immunohistochemistry is only a semiquantitative assessment of the amount of cytokine, and gives a relative measurement implying that comparisons between the various cytokines are not possible.…”

Section: Discussionsupporting

confidence: 58%

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

et al. 2007

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-Twelve healthy primiparous sows received intramammary inoculation with Escherichia coli (serotype O127) during the 24-h period preceding parturition. Mammary gland biopsy samples were taken immediately before inoculation (0 h) and from the inoculated and the contralateral noninoculated glands 24 h after inoculation. The analyses of interleukin-1 beta (IL-1β), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) by immunohistochemistry revealed that the production of these proinflammatory cytokines significantly increased in the inoculated mammary glands of sows that developed clinical signs of mastitis (affected group, n = 4) 24 h after inoculation. This was also true for IL-8 in the inoculated mammary glands of sows that did not develop clinical signs of mastitis (nonaffected group, n = 8). Sows that developed clinical signs of mastitis displayed significantly lower constitutive production of IL-1β than did sows that remained clinically healthy. The data indicate that the development of clinical symptoms of coliform mastitis in the sow is associated with a locally increased proinflammatory cytokine production in response to intramammary E. coli infection.cytokine / immunohistochemistry / mastitis / pig / E. coli

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Section: Discussionsupporting

confidence: 58%

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

et al. 2007

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“…This increased cytokine secretion is possibly due to the ineffective CTL activation and granule exocytosis and a resulting positive feedback loop on cytokine secretion. Since both IFN-γ and TNF are defectively secreted in Stx11 −/− CTLs, we can suggest that a dysregulated cytokine release applies to cytokines described to follow a directed secretion to the immunological synapse, such as IFN-γ [31] or towards phagocytic cups in activated macrophages, such as TNF [32]. Thus, we cannot exclude any specific and unique role of STX11 in regulating distinct secretion of cytokines polarized pathways.…”

Section: Discussionmentioning

confidence: 92%

Syntaxin 11 is required for NK and CD8⁺ T‐cell cytotoxicity and neutrophil degranulation

et al. 2012

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Syntaxin 11 (STX11) controls vesicular trafficking and is a key player in exocytosis. SinceStx11 mutations are causally associated with a familial hemophagocytic lymphohistiocytosis, we wanted to clarify whether STX11 is functionally important for key immune cell populations. This was studied in primary cells obtained from newly generated Stx11 −/− mice. Our data revealed that STX11 is not only widely expressed in different immune cells, but also induced upon LPS or IFN-γ treatment. However, Stx11 deficiency does not affect macrophage phagocytic function and cytokine secretion, mast cell activation, or antigen presentation by DCs. Instead, STX11 selectively controls lymphocyte cytotoxicity in NK and activated CD8 + T cells and degranulation in neutrophils. Stx11 −/− NK cells and CTLs show impaired degranulation, despite a comparable activation, maturation and expression of the complex-forming partners MUNC18-2 and VTI1B. In addition, Stx11 −/− CTLs and NK cells produce abnormal levels of IFN-γ. Since functional reconstitution rescues the defective phenotype of Stx11 −/− CTLs, we suggest a direct, specific and key role of STX11 in controlling lymphocyte cytotoxicity, cytokine production and secretion. Finally, we show that these mice are a very useful tool for dissecting the role of STX11 in vesicular trafficking and secretion. Keywords: CTL r Cytokines r Exocytosis r N-ethylmaleimide-sensitive factor attachment protein receptorSee accompanying Commentary by Lopez and Voskoboinik.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSyntaxin 11 (STX11) belongs to the family of N-ethylmaleimidesensitive factor attachment protein receptor (SNARE) proteins Correspondence: Prof. Silvia Bulfone-Paus e-mail: sbulfone@fz-borstel.de and is involved in intracellular membrane trafficking events by interacting with other family members or by associating with membranes by palmitoylation of cysteine residues [1][2][3]. STX11 is expressed in a wide variety of cells including human monocytes/macrophages, neutrophils, B cells, NK cells and CD8 + T cells [2][3][4][5][6][7][8][9]. STX11 is enriched in immune tissues such as thymus, spleen C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 194-208 Immunomodulation 195 Values represent the mean ± SEM percentage of cell subsets in the spleen (n = 8) and lymph nodes (WT n = 7; Stx11 −/− n = 6) and are the summary of three experiments performed.and lymph nodes, but lower levels of protein are detectable also in heart, kidney and liver [2]. STX11 localizes mainly in the vesicular tubular clusters, an organelle complex between the endoplasmic reticulum and the Golgi, and displays, in addition, a spotted staining pattern throughout the cell periphery [2,9]. While STX11 has been recognized to act as a negative regulator of both phagocytosis and intracellular trafficking between endosomes, lysosomes and the outer membrane in macrophages [6,9], in human NK cells and CTLs, ST...

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“…TGF-␤ has paracrine effects that enable T cells to up-regulate production of this cytokine (46,47), and the presence of TGF-␤ at the onset of the cultures induced production of this cytokine. Moreover, it is now appreciated that T cells not only release cytokines into the microenvironment, but also secrete them into immunological synapses where they can modulate TCR signaling (48). This contact-dependent cytokine effect may explain why anti-TGF-␤ blocks the generation of secondarily induced Treg cells before secretion of this cytokine became detectable (49).…”

Section: Discussionmentioning

confidence: 99%

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

Zheng

Wang

et al. 2007

The Journal of Immunology

537

418

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IL-2 and TGF-β both have important roles in the induction and maintenance of immunologic tolerance, but whether these cytokines act separately or together to achieve this effect is poorly understood. Although others have reported that IL-2 can directly enhance forkhead box protein P3 (Foxp3) transcription factor expression by natural CD4+CD25+ regulatory T cells, in this study, we report that the role of IL-2 on the generation of peripheral regulatory CD4+ cells is indirect. Ab neutralization studies and experiments with IL-2-deficient mice have revealed that IL-2 is required for TGF-β to induce naive CD4+CD25− cells to become CD25+ and express Foxp3, and develop the characteristic properties of CD4+CD25+ regulatory cells. This effect of IL-2 on the generation and expansion of these adaptive Foxp3+ regulatory cells is nonredundant, but IL-4, IL-7, and IL-15, other common γ-chain cytokines, could sustain Foxp3 expression. Because subjects with autoimmune diseases often have defects in the production of IL-2 and/or TGF-β, the generation of autologous T regulatory cells ex vivo with these cytokines for transfer in vivo may have considerable therapeutic potential.

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T cells use two directionally distinct pathways for cytokine secretion

Cited by 399 publications

References 52 publications

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

Syntaxin 11 is required for NK and CD8⁺ T‐cell cytotoxicity and neutrophil degranulation

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

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T cells use two directionally distinct pathways for cytokine secretion

Cited by 399 publications

References 52 publications

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

Syntaxin 11 is required for NK and CD8+ T‐cell cytotoxicity and neutrophil degranulation

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

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Syntaxin 11 is required for NK and CD8⁺ T‐cell cytotoxicity and neutrophil degranulation