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

Giangreco, Adam; Hoste, Esther; Takai, Yoshimi; Rosewell, Ian; Watt, Fiona M.

doi:10.4049/jimmunol.1003342

Cited by 18 publications

(17 citation statements)

References 34 publications

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“…While we have not directly shown that Cadm1 expression resulted in tumor cell death by T cells, this notion is supported by previous studies [20], [21] showing Cadm1 expression on target cells enhances T cell cytotoxicity in an MHC-dependent manner. Thus loss or reduction in Cadm1 expression may contribute to the final step of cancer immunoediting: tumor cell “escape” from detection by the immune system [31].…”

Section: Discussionsupporting

confidence: 72%

“…The engagement of Cadm1 on tumor cells and Crtam on CD8 + T cells has been reported to induce interferon-γ production of CD8 + T cells [20], [21]. We hypothesized that enhanced interferon-γ may mediate an inflammatory response to induce tumor cytotoxicity.…”

Section: Resultsmentioning

confidence: 96%

“…This interaction has been shown to induce interferon-γ production by CD8 + T cells, enhance CD8 + T cell and NK-cell cytotoxicity in vitro , and tumor rejection in vivo [20], [21]. In order to test the role of cell-mediated immunity in Cadm1 -mediated metastasis suppression, control and Cadm1 -expressing cells were orthotopically implanted into athymic nude mice.…”

Section: Resultsmentioning

confidence: 99%

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Cadm1 Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity

et al. 2012

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Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell–mediated immunity, which was partially phenocopied by depleting CD8+ T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.

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Section: Discussionsupporting

confidence: 72%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

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Cadm1 Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity

et al. 2012

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“…Family members include SRY-related Sox genes that are implicated in skeletal dysplasias [37], [38] and the TCF/LEF transcription factors that mediate Wnt/β-catenin signaling [39], a key pathway implicated in osteoporosis and osteoarthritis [40]–[43]. Cadm1 encodes a trans-membrane glycoprotein adhesion molecule of the immunoglobulin superfamily [44] for which a number of disparate functions have been reported including; tumor suppression [45], synapse development [46], behavioral regulation [47], T cell adhesion [48], mast cell interactions [49], and spermatogenesis [50]. However, no function in the skeleton has been reported.…”

Section: Discussionmentioning

confidence: 99%

Rapid-Throughput Skeletal Phenotyping of 100 Knockout Mice Identifies 9 New Genes That Determine Bone Strength

et al. 2012

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Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium.

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“…Alopecia areata (AA) is an autoimmune nonscarring hair loss disorder affecting up to 2% of people worldwide [1]. The hair loss phenotype is usually induced by an inflammatory infiltrate, predominantly comprising CD4+ and CD8+ lymphocytes [2].…”

Section: Introductionmentioning

confidence: 99%

SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction

Gao

Jin

2017

Oncotarget

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Alopecia areata is one of the most common autoimmune diseases resulting from T cell-mediated damage of hair follicles. CD8+ T cells infiltrate hair follicles and are responsible for destruction of hair follicles. However the underlying mechanisms for hair loss remain still obscure. In the present study, we identified that suppressor of cytokine signaling-3 (SOCS3), a classical inhibitor of cytokine signaling, significantly inhibits CD8+T cell maturation, interferon-γ (IFN-γ) production and alopecia areata. SOCS3 is downregulated in the skin of alopecia areata patients and murine autoimmune alopecia model. Furthermore, SOCS3 treatment prevents the development of alopecia areata in the graft model. SOCS3 decreases the CD44high CD62Llow effector memory CD8+ T cells, resulting in the decrease of IFN-γ production. The expression of Fas and major histocompatibility complex-1 (MHC I) is upregulated in skin from C3H/HeJ alopecia areata mice, and this increase is suppressed by SOCS3. The SOCS3 level is negative correlation with the Fas and MHC I level in patients with alopecia areata. These results suggest that SOCS3 treatment may be an effective strategy to treat autoimmune alopecia as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.

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

Cited by 18 publications

References 34 publications

Cadm1 Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity

Cadm1 Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity

Rapid-Throughput Skeletal Phenotyping of 100 Knockout Mice Identifies 9 New Genes That Determine Bone Strength

SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction

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