Structural understanding of T cell receptor triggering

Xu, Xiaoxiao; Li, Hua; Xu, Chenqi

doi:10.1038/s41423-020-0367-1

Cited by 38 publications

(24 citation statements)

References 133 publications

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“…The TCR/CD3 complex is consist of multiple building blocks including TCRαβ, CD3ζζ, CD3δε, and CD3γε. The TCRαβ heterodimer is an antigen-binding subunit and lacks inherent signal-transducing domain, whereas CD3 subunits contain the immunoreceptor tyrosine-based activation motif (ITAM) which could be phosphorylated and responsible for the signal transduction from TCR to intracellular pathways ( Pitcher and van Oers, 2003 ; Kuhns et al, 2006 ; Xu et al, 2020 ). To test whether the TCR/CD3 complex is required for fucoidan to stimulate T cells, we suppressed CD3E expression using targeted shRNAs, as the encoded CD3ε is critical for T cell activation ( Gil et al, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity

Yang

Pan

et al. 2021

Front. Cell Dev. Biol.

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Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies in vivo. Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8+ T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8+ T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer.

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Section: Discussionmentioning

confidence: 99%

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity

Yang

Pan

et al. 2021

Front. Cell Dev. Biol.

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“…It is known, however, that the TREM2 co-receptor DNAX Activating Protein of 12 kDa (DAP12) becomes phosphorylated on intracellular tyrosine residues. An analogous signal propagation occurs in the T-cell receptor, but even in this well-studied example, with many available structures, not all of the aspects of the molecular details are known [61]. In the context of microglia, the kinase responsible for phosphorylating the Immunoreceptor Tyrosine Activation Motif (ITAM) residues on DAP12 is likely to be Src [62] or a Src-family kinase such as Lyn [63,64].…”

Section: Microglia Signalling Network: Linking Trem2 To Plcγ2 a Paramentioning

confidence: 99%

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

Magno

Bunney

Mead

et al. 2021

Mol Neurodegeneration

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The central role of the resident innate immune cells of the brain (microglia) in neurodegeneration has become clear over the past few years largely through genome-wide association studies (GWAS), and has rapidly become an active area of research. However, a mechanistic understanding (gene to function) has lagged behind. That is now beginning to change, as exemplified by a number of recent exciting and important reports that provide insight into the function of two key gene products – TREM2 (Triggering Receptor Expressed On Myeloid Cells 2) and PLCγ2 (Phospholipase C gamma2) – in microglia, and their role in neurodegenerative disorders. In this review we explore and discuss these recent advances and the opportunities that they may provide for the development of new therapies.

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“…The myeloid-specific genes ITGAM and PU.1 ( Pahl et al, 1993 ) were both co-expressed in populations A and B ( Figure 1C ). The T cell-specific genes CD3 and TCRa ( Xu et al, 2020 ) were enriched in population C as was the T-cell associated gene perforin. The B cell-specific genes IGHM and IG-lambda-Constant chain ( Andre et al, 2000 ) were only enriched in population D and E. RAG-1 is a gene involved in T and B cell development and is downregulated during maturation ( Durand et al, 2000 ).…”

Section: Resultsmentioning

confidence: 99%

Identification of the Adult Hematopoietic Liver as the Primary Reservoir for the Recruitment of Pro-regenerative Macrophages Required for Salamander Limb Regeneration

Debuque

Hart

Johnson

et al. 2021

Front. Cell Dev. Biol.

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The lack of scar-free healing and regeneration in many adult human tissues imposes severe limitations on the recovery of function after injury. In stark contrast, salamanders can functionally repair a range of clinically relevant tissues throughout adult life. The impressive ability to regenerate whole limbs after amputation, or regenerate following cardiac injury, is critically dependent on the recruitment of (myeloid) macrophage white blood cells to the site of injury. Amputation in the absence of macrophages results in regeneration failure and scar tissue induction. Identifying the exact hematopoietic source or reservoir of myeloid cells supporting regeneration is a necessary step in characterizing differences in macrophage phenotypes regulating scarring or regeneration across species. Mammalian wounds are dominated by splenic-derived monocytes that originate in the bone marrow and differentiate into macrophages within the wound. Unlike mammals, adult axolotls do not have functional bone marrow but instead utilize liver and spleen tissues as major sites for adult hematopoiesis. To interrogate leukocyte identity, tissue origins, and modes of recruitment, we established several transgenic axolotl hematopoietic tissue transplant models and flow cytometry protocols to study cell migration and identify the source of pro-regenerative macrophages. We identified that although bidirectional trafficking of leukocytes can occur between spleen and liver tissues, the liver is the major source of leukocytes recruited to regenerating limbs. Recruitment of leukocytes and limb regeneration occurs in the absence of the spleen, thus confirming the dependence of liver-derived myeloid cells in regeneration and that splenic maturation is dispensable for the education of pro-regenerative macrophages. This work provides an important foundation for understanding the hematopoietic origins and education of myeloid cells recruited to, and essential for, adult tissue regeneration.

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Structural understanding of T cell receptor triggering

Cited by 38 publications

References 133 publications

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

Identification of the Adult Hematopoietic Liver as the Primary Reservoir for the Recruitment of Pro-regenerative Macrophages Required for Salamander Limb Regeneration

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