Dataset Information

??TCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program.

ABSTRACT: ??T cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing ??T (??T17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for ??TCR signal transduction and development of ??T17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of ??T cells, failed to functionally substitute for Syk in the development of ??T17. Syk induced the activation of the PI3K/Akt pathway upon ??TCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of ??T17, without impaired development of IFN-?-producing ??T cells. Moreover, ??T17-dependent skin inflammation was ameliorated in mice deficient in RhoH, an adaptor known to recruit Syk. Thus, we deciphered lineage-specific TCR signaling and identified the Syk/PI3K pathway as a critical determinant of proinflammatory ??T cell differentiation.

SUBMITTER: Muro R

PROVIDER: S-EPMC5749532 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program.

Muro Ryunosuke R Nitta Takeshi T Nakano Kenta K Okamura Tadashi T Takayanagi Hiroshi H Suzuki Harumi H

The Journal of clinical investigation 20171204 1

γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development ...[more]

PMID: 29202478

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Project description:UNLABELLED:Chitin is an important cell wall component of Aspergillus fumigatus conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from Aspergillus fumigatus Transcription and production of the proinflammatory cytokine interleukin-1? (IL-1?) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively. Chitin induced an anti-inflammatory signature characterized by the production of IL-1Ra in the presence of human serum, which was abrogated in immunoglobulin-depleted serum. Fc-?-receptor-dependent recognition and phagocytosis of IgG-opsonized chitin was identified as a novel IL-1Ra-inducing mechanism by chitin. IL-1Ra production induced by chitin was dependent on Syk kinase and phosphatidylinositol 3-kinase (PI3K) activation. In contrast, costimulation of chitin with the pattern recognition receptor (PRR) ligands lipopolysaccharide, Pam3Cys, or muramyl dipeptide, but not ?-glucan, had synergistic effects on the induction of proinflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In conclusion, chitin can have both pro- and anti-inflammatory properties, depending on the presence of pathogen-associated molecular patterns and immunoglobulins, thus explaining the various inflammatory signatures reported for chitin. IMPORTANCE:Invasive aspergillosis and allergic aspergillosis are increasing health care problems. Patients get infected by inhalation of the airborne spores of Aspergillus fumigatus A profound knowledge of how Aspergillus and its cell wall components are recognized by the host cell and which type of immune response it induces is necessary to develop target-specific treatment options with less severe side effects than the treatment options to date. There is controversy in the literature about the receptor for chitin in human cells. We identified the Fc-? receptor and Syk/PI3K pathway via which chitin can induce anti-inflammatory immune responses by inducing IL-1 receptor antagonist in the presence of human immunoglobulins but also proinflammatory responses in the presence of bacterial components. This explains why Aspergillus does not induce strong inflammation just by inhalation and rather fulfills an immune-dampening function. While in a lung coinfected with bacteria, Aspergillus augments immune responses by shifting toward a proinflammatory reaction.

Dataset Information

??TCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program.

Publications

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program.

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