FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

Chauhan, Anil K.; Moore, Terry L.; Bi, Ye; Chen, Chen

doi:10.1074/jbc.m115.684795

Cited by 20 publications

(51 citation statements)

References 86 publications

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“…TLR9 staining was performed and confirmed using two monoclonal antibody conjugates anti-TLR9-PE (eBioscience) and anti-TLR9-APC (BD Biosciences, clone eB72-1665). For studying the effect of CpG ODN 2006, cells were stimulated and polarized in the presence of IL-1β, IL-6, IL-23, and TGF-β as reported by us earlier (19). Purified naïve CD4 + T-cells at a density of 0.25 M cells/well were plated in 96-well plates (Nunc) and activated as previously reported (19, 22).…”

Section: Methodsmentioning

confidence: 99%

“…Enhanced presence of NA-TLRs on the CD4 + T-cell surface can establish a cross-talk, which raises the possibility of synergized signaling with either the TCR and/or FcRs. We have earlier shown that the phosphorylation of spleen tyrosine kinase (Syk) by FcγRIIIa triggers the differentiation of human naïve CD4 + T-cells into proinflammatory IFN-γ and IL-17A producing effector T-cells (T E ) (19–22). FcγRIIIa-pSyk cosignaling also induces expression of NA-TLRs and type 1 interferon (IFN) RNA transcripts (19).…”

Section: Introductionmentioning

confidence: 99%

“…We have earlier shown that the phosphorylation of spleen tyrosine kinase (Syk) by FcγRIIIa triggers the differentiation of human naïve CD4 + T-cells into proinflammatory IFN-γ and IL-17A producing effector T-cells (T E ) (19–22). FcγRIIIa-pSyk cosignaling also induces expression of NA-TLRs and type 1 interferon (IFN) RNA transcripts (19). The role for FcγRIIIa-pSyk as a costimulatory signal in NA-TLR responses that contribute to the CD4 + T-cell differentiation has never been investigated.…”

Section: Introductionmentioning

confidence: 99%

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FcγRIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells

Chauhan

2017

The Journal of Immunology

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Summary Recognition of antibody-opsonized pathogens by immune cells triggers both toll-like receptor (TLR) and Fc-receptor (FcR) signaling. FcRs endocytose modified nucleic acids bound to antibodies and deliver them to endosomes, where they are recognized by nucleic acid-sensing TLRs (NA-TLRs). We show that in CD4+ T-cells NA-TLRs, TLR3, TLR8 and TLR9 are upregulated by FcγRIIIa-pSyk cosignaling and localize with FcγRIIIa on the cell surface. TLR9 accumulates on the cell surface, where it recognizes CpG oligonucleotide (ODN) 2006. Subcellular location of NA-TLRs is a key determinant in discriminating self vs. viral nucleic acid. Hydroxychloroquine used for treating systemic lupus erythematosus and a Syk inhibitor blocked NA-TLR localization with FcγRIIIa. Engaging TLR9 with CpG ODN contributes to the development of IL17A+ and IL-21+ populations. RNA-seq analysis showed up-regulation of proinflammatory cytokines, NF-κB signaling and heat shock protein pathway RNA transcripts. These data suggest a role for FcγRIIIa-pSyk cosignaling in modulating NA-TLR responses in human CD4+ T-cells by affecting the amounts and cellular distribution. These events are important for understanding of autoimmune pathology.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FcγRIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells

Chauhan

2017

The Journal of Immunology

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“…2). Stimulation of SLE T cells through TLR2, a molecule increased in SLE CD4 T cells upon activation of the Syk pathway [28], leads to chromatin opening at the promoters of IL-17A and IL-17F through increased histone acetylation and reduced DNA methylation [29], and activates NF-κB [30]. The protein phosphatase (PP) 2A is increased in SLE T cells; it also controls the IL-17 promoter, inducing hypomethylation by suppressing the DNA methyltransferase 1 pathway, promoting acetylation of histone 3 [31,32], and facilitating the binding of IRF4 which is activated by Rho-associated protein kinase (ROCK)[33].…”

Section: Increased Numbers Of T Helper 17 Cells Promote Kidney Diseasmentioning

confidence: 99%

T cells in Systemic Lupus Erythematosus

Suárez‐Fueyo

Bradley

Tsokos

2016

Current Opinion in Immunology

177

127

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Systemic Lupus Erythematosus is an autoimmune disorder caused by a complex combination of genetic, epigenetic and environmental factors. Different polymorphisms and epigenetic modifications lead to altered gene expression and function of several molecules which lead to abnormal T cell responses. Metabolic and functional alterations result in peripheral tolerance failures and biased differentiation of T cells into pro-inflammatory and B cell-helper phenotypes as well as the accumulation of disease-promoting memory T cells. Understanding these T cell alterations and their origins is necessary to develop more accurate patient classification systems and to discover new therapeutic targets.

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“…The microarray data also confirmed that the tyrosine kinases, TAM family receptor tyrosine kinase TYRO3 and SYK, are upregulated in the Helios-1 overexpressed Jurkat T-cells. The TYRO3 functions as a negative regulator of type 2 immunity (26), whereas the SYK has the ability to modulate the CD4 + T cell response (27). The GO analysis indicates that the pathways of the immune effector process and immune response (for example IL28, IL36, and TLR3) are enriched in the Helios-1 T cells.…”

Section: Discussionmentioning

confidence: 99%

Role of a non-canonical splice variant of the Helios gene in the differentiation of acute lymphoblastic leukemic T cells

Liu

et al. 2018

Oncol Lett

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Abstract. T-cell acute lymphoblastic leukemia is a hematopoietic malignant disease, which arises from a genetic defect in the T-cell maturation signaling pathway. As a result, it is necessary to identify the molecules that impact T-cell development and control lymphoid-lineage malignancy. The present study utilized Jurkat T lymphoblastic cells as a well-established approach for the investigation into the function of the non-canonical alternative splice variant of Helios for the in vitro study of T-cell differentiation and leukemogenesis. In the present study, the Jurkat T-cell lines with stable overexpression of the wild-type (Helios-1) or the non-canonical short isoform (Helios-Δ326-1431), were established. RNA microarray, reverse transcription-quantitative polymerase chain reaction and flow cytometry were used to assess changes in the gene expression profiles and to monitor the cell surface markers during T-cell differentiation. Multiple genes associated with T-cell differentiation and leukemogenesis were identified as being either activated or suppressed. In addition, the results indicated that the stable overexpression of the Helios isoforms stimulated the differentiation pathway of the T-lineage lymphoblastic cells. Therefore, these results suggest that full-length Helios-1 has a tumor suppressor-like and immunomodulatory role, in contrast to the oncogenic function of the non-canonical short isoform

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FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

Abstract: CD4؉

Cited by 20 publications

References 86 publications

FcγRIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells

FcγRIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells

T cells in Systemic Lupus Erythematosus

Role of a non-canonical splice variant of the Helios gene in the differentiation of acute lymphoblastic leukemic T cells

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