IGSF4 is a novel TCR ζ-chain–interacting protein that enhances TCR-mediated signaling

Kim, Hye Ran; Jeon, Byeong Hun; Lee, Hyun Su; Im, Sin Hyeog; Araki, Masatake; Araki, Kimi; Yamamura, Ken Ichi; Choi, Suck Chei; Park, Do‐Sim; Jun, Chang Duk

doi:10.1084/jem.20110853

Cited by 19 publications

(24 citation statements)

References 48 publications

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“…FcRIII, IGSF4 [43], NKp30, NKp46) associate with the -chain and therefore the predictions made here may be applicable to these receptors. There are many other receptors, termed Non-catalytic Tyrosine-Phosphorylated Receptors (NTRs) [44], with multiple phosphorylation sites that are regulated by extrinsic enzymes and like the TCR, spurious activation of these receptors may be avoided by switch-like responses that contain strong thresholds.…”

Section: Discussionmentioning

confidence: 69%

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

et al. 2013

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Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy.

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Section: Discussionmentioning

confidence: 69%

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

et al. 2013

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“…Cadm1-CRTAM adhesion promotes Cadm1-expressing tumor cell immunosurveillance and tumor cell clearance (22), as well as latestage T cell maturation within secondary lymphoid tissues (15,17,23,24). Cadm1 has also been shown recently to interact with the z-chain of the TCR, enhancing TCR activation and promoting T cell interactions with APCs (31). Taken together with our observations, these findings suggest that CRTAM-Cadm1 interactions in both lymph nodes and target tissues are involved in a variety of different autoimmune disorders.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Cadm1 Expression Promotes Autoimmune Alopecia via Enhanced T Cell Adhesion and Cytotoxicity

Giangreco

Hoste

Takai

et al. 2012

The Journal of Immunology

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Autoimmune alopecia is characterized by an extensive epidermal T cell infiltrate that mediates hair follicle destruction. We have investigated the role of cell adhesion molecule 1 (Cadm1; Necl2) in this disease. Cadm1 is expressed by epidermal cells and mediates heterotypic adhesion to lymphocytes expressing class 1-restricted T cell-associated molecule (CRTAM). Using a murine autoimmune alopecia model, we observed an increase in early-activated cytotoxic (CD8-restricted, CRTAM-expressing) T cells, which preferentially associated with hair follicle keratinocytes expressing Cadm1. Coculture with Cadm1-transduced MHC-matched APCs stimulated alopecic lymph node cells to release IL-2 and IFN-γ. Overexpression of Cadm1 in cultured human keratinocytes did not promote cytokine secretion, but led to increased adhesion of alopecic cytotoxic T cells and enhanced T cell cytotoxicity in an MHC-independent manner. Epidermal overexpression of Cadm1 in transgenic mice led to increased autoimmune alopecia susceptibility relative to nontransgenic littermate controls. Our findings reveal that Cadm1 expression in the hair follicle plays a role in autoimmune alopecia.

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“…45 CD3-z chain, as an integral component of T-cell receptor (TCR) complex, is important for competent signaling after TCR-MHC-peptide interactions and T cell activation. 46 Exosomal TNF-a from cancer cells affected TCR-CD3 complex by a reactive oxygen species way. As a result, signals to activate CD4 C and CD8 C T cells were disrupted.…”

Section: Impairment Of Ctl Response and Induction Of Regulatory T Cellsmentioning

confidence: 99%

The exosomes in tumor immunity

2015

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Exosomes are a kind of nanometric membrane vesicles and can be released by almost all kinds of cells, including cancer cells. As the important mediators in intercellular communications, exosomes mediate exchange of protein and genetic material derived from parental cells. Emerging evidences show that exosomes secreted by either host cells or cancer cells are involved in tumor initiation, growth, invasion and metastasis. Moreover, communications between immune cells and cancer cells via exosomes play dual roles in modulating tumor immunity. In this review, we focus on exosome-mediated immunosuppression via inhibition of antitumor responses elicited by immune cells (DCs, NK cells, CD4 C and CD8 C T cells, etc.) and induction of immunosuppressive or regulatory cell populations (MDSCs, Tregs and Bregs). Transfer of cytokines, microRNAs (miRNAs) and functional mRNAs by tumor-derived exosomes (TEXs) is crucial in the immune escape. Furthermore, exosomes secreted from several kinds of immune cells (DCs, CD4 C and CD8 C Tregs) also participate in immunosuppression. On the other hand, we summarize the current application of DCderived and modified tumor-derived exosomes as tumor vaccines. The potential challenges about exosome-based vaccines for clinical application are also discussed.

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IGSF4 is a novel TCR ζ-chain–interacting protein that enhances TCR-mediated signaling

Abstract: The expression of cell surface molecule, IGSF4, on human and mouse T cells associate with the TCR ζ-chain and colocalizes to the c-SMAC to enhance cytokine production and adhesion to APCs.

Cited by 19 publications

References 48 publications

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

Epidermal Cadm1 Expression Promotes Autoimmune Alopecia via Enhanced T Cell Adhesion and Cytotoxicity

The exosomes in tumor immunity

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