TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

González‐Navajas, José M.; Fine, Sean; Law, Jason; Datta, Sandip K.; Nguyen, Kim; Yu, Mandy; Corr, Maripat; Katakura, Kyoko; Eckman, Lars; Lee, Jongdae; Raz, Eyal

doi:10.1172/jci40055

Cited by 132 publications

(142 citation statements)

References 51 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…17 Alternatively, TLR4 expressing CD4+ T-cells signal via the MAPK pathway to induce tonic inhibitory signals in mice. 18 Therefore, we speculate that epigenetic disruption of the MAPK pathway may produce suboptimal signaling leading to the dysregulated CD4+ T-cell responses previously observed in this cohort. Further work is needed to address this specific hypothesis, particularly since these pathways are also regulated post-transcriptionally.…”

Section: Discussionmentioning

confidence: 79%

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

et al. 2014

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 79%

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

et al. 2014

View full text Add to dashboard Cite

“…However, development of colitis itself was not blocked in MD-2/MDR1A dKO mice, implying that MD-2 signaling is required for the progression but not for the initiation of colitis in MDR1A deficiency. Notably, others have recently shown that LPS signaling via TLR4 protects against acute DSS colitis (63, 64) and chronic colitis in IL-10-null mice (65,66). Thus, LPS signaling can be either protective or destructive in the intestinal mucosa, depending on the genetic context.…”

Section: Discussionmentioning

confidence: 99%

Loss of TLR2 Worsens Spontaneous Colitis in MDR1A Deficiency through Commensally Induced Pyroptosis

Eyking

Klepak

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b+ myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1β activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b+Ly6C+-derived IL-1β production and inflammation entirely depended on MyD88. TLR2/MDR1A double-knockout CD11b+ myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1β, consistent with pyroptosis. Inhibition of reactive oxygen species–mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis.

show abstract

“…Colitis was induced by adoptive transfer of naive CD45RB hi CD4 + T cells: sorted naive CD4 + T cells (CD4 + CD45RB hi CD25 -, 1 × 10 5 cells/mouse) from WT or Gnas ΔCD4 spleen were adoptively transferred into 12-week-old sex- and age-matched Rag1 -/-mice as described previously (37). A group of Rag1 -/-mice also received 0.5 × 10 5 CD45RB lo CD25 + (Tregs) from WT mice; naive CD4 + T cells (1 × 10 5 cells) were used controls.…”

Section: Methodsmentioning

confidence: 99%

“…Splenic and mesenteric lymph node (MLN) cells were cultured in RPMI-1640 medium and stimulated by PMA/ionomycin for 5 hours in the presence of GolgiStop (BD Biosciences - Pharmingen) for intracellular staining. The colon explants were isolated and cultured as described previously (37), and cytokines levels in the supernatant were measured (ELISA).…”

Section: Methodsmentioning

confidence: 99%

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

Li¹,

Murray²,

Koide³

et al. 2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

cAMP, the intracellular signaling molecule produced in response to GPCR signaling, has long been recognized as an immunosuppressive agent that inhibits T cell receptor activation and T cell function. However, recent studies show that cAMP also promotes T cell-mediated immunity. Central to cAMP production downstream of GPCR activation is the trimeric G protein Gs. In order to reconcile the reports of divergent effects of cAMP in T cells and to define the direct effect of cAMP in T cells, we engineered mice in which the stimulatory Gα subunit of Gs (Gαs) could be deleted in T cells using CD4-Cre (Gnas ΔCD4 ). Gnas ΔCD4 CD4 + T cells had reduced cAMP accumulation and Ca 2+ influx. In vitro and in vivo, Gnas ΔCD4 CD4 + T cells displayed impaired differentiation to specific Th subsets: Th17 and Th1 cells were reduced or absent, but Th2 and regulatory T cells were unaffected. Furthermore, Gnas ΔCD4 CD4 + T cells failed to provoke colitis in an adoptive transfer model, indicating reduced inflammatory function. Restoration of cAMP levels rescued the impaired phenotype of Gnas ΔCD4

show abstract

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

Cited by 132 publications

References 51 publications

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Loss of TLR2 Worsens Spontaneous Colitis in MDR1A Deficiency through Commensally Induced Pyroptosis

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

Contact Info

Product

Resources

About