<i>In vivo </i>CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

Marhaba, Rachid; Freyschmidt‐Paul, Pia; Zöller, Margot

doi:10.1002/eji.200636158

Cited by 31 publications

(37 citation statements)

References 67 publications

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“…Although we did not observe a direct association between CD44 and PI3K, this does not exclude PI3K activation by downstream signals of CD44. Signals possibly could be transmitted through CD44-associated integrins (42), which can be activated via CD44v ligand binding (27). In fact, CD44 is associated with a 3 and h 1 integrin chains in ASML wt cells, but cross-linking of a 3 or h 1 does not promote PI3K/Akt activation (data not shown).…”

Section: Cd44v and Apoptosis Protectionmentioning

confidence: 92%

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Klingbeil

Marhaba

Jung

et al. 2009

Molecular Cancer Research

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CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44v kd ) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML wt ) were established. ASML-CD44v kd clones hardly form lung metastases after intrafootpad application and the metastatic load in lymph nodes is significantly reduced. Rescuing, albeit at a reduced level, CD44v expression in ASML-CD44v kd cells (ASML-CD44v rsc ) restores the metastatic potential. The following major differences in ASML wt , ASML-CD44v kd , and ASML-CD44v rsc clones were observed: (a) ASML wt cells produce and assemble a matrix in a CD44v-dependent manner, which supports integrin-mediated adhesion and favors survival. This feature is lost in the ASML-CD44v kd cells. (b) CD44v cross-linking initiates phosphatidylinositol 3-kinase/Akt activation in ASML wt cells. Accordingly, apoptosis resistance is strikingly reduced in ASML-CD44v kd cells. The capacity to generate an adhesive matrix but not apoptosis resistance is restored in ASML-CD44v rsc cells. These data argue for a 2-fold effect of CD44v on metastasis formation: CD44v-mediated matrix formation is crucial for the settlement and growth at a secondary site, whereas apoptosis resistance supports the efficacy of metastasis formation.

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Section: Cd44v and Apoptosis Protectionmentioning

confidence: 92%

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Klingbeil

Marhaba

Jung

et al. 2009

Molecular Cancer Research

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“…AA is characterized by a strong increase in highly activated SkIL and skin draining LNC (38). A therapeutic effect of a contact sensitizer requires repeated application for a prolonged period (35).…”

Section: Characterization Of Mdsc In Aa and Aa/dth Micementioning

confidence: 99%

The Importance of Myeloid-Derived Suppressor Cells in the Regulation of Autoimmune Effector Cells by a Chronic Contact Eczema

Marhaba

Vitacolonna

Hildebrand

et al. 2007

The Journal of Immunology

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Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4+CD25high lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4+CD25+ T cells. Instead, a population of Gr-1+CD11b+ cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1+CD11b+ spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-γ receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1+ cells expressed several chemokines and CCR8 at high levels. Gr-1+CD11b+ cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4+ or CD8+ cells from AA mice, the Gr-1+CD11b+ cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, ζ-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via ζ-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.

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“…The cell surface CD44 levels are elevated in activated T cells (6). Via its interactions with endothelial hyaluronan, CD44 functions as a prominent adhesion receptor in autoimmune T cell adhesion on the endothelium and the subsequent transmigration events (7)(8)(9)(10)(11).…”

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confidence: 99%

Specific Inhibition of Autoimmune T Cell Transmigration Contributes to β Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice

Savinov

Rozanov

Strongin

2007

Journal of Biological Chemistry

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Human diabetes mellitus (IDDM; type I diabetes) is a T cellmediated disease that is closely modeled in non-obese diabetic (NOD) mice. The pathogenesis of IDDM involves the transmigration of autoimmune T cells into the pancreatic islets and the subsequent destruction of insulin-producing ␤ cells. Therapeutic interventions leading to ␤ cell regeneration and the reversal of established IDDM are exceedingly limited. We report here that specific inhibition of T cell intra-islet transmigration by using a small molecule proteinase inhibitor restores ␤ cell functionality, increases insulin-producing ␤ cell mass, and alleviates the severity of IDDM in acutely diabetic NOD mice. As a result, acutely diabetic NOD mice do not require insulin injections for survival for a significant time period, thus providing a promising clue to effect IDDM reversal in humans. The extensive morphometric analyses and the measurements of both the C-peptide blood levels and the proinsulin mRNA levels in the islets support our conclusions. Diabetes transfer experiments suggest that the inhibitor specifically represses the T cell transmigration and homing processes as opposed to causing immunosuppression. Overall, our data provide a rationale for the pharmacological control of the T cell transmigration step in human IDDM.The pathogenesis of IDDM 2 involves the activation of autoimmune T killer cells. Activated autoimmune T cells transmigrate from the bloodstream through the pancreatic endothelium and into the islets of Langerhans, where they destroy insulin-producing ␤ cells. We suggested and then proved in our current work that the inhibition of T cell transmigration and homing would effectively control islet destruction and stimulate the functional recovery of the insulin-producing ␤ cells and the regeneration of the pancreatic islets.Mice of the NOD inbred strain develop a spontaneous disease closely resembling human IDDM and have been widely and successfully used as a model of IDDM (1-3). CD8ϩ T lymphocytes are involved in diabetogenesis in NOD mice; mice lacking CD8 ϩ T cells do not develop diabetes (4, 5). The cell surface CD44 levels are elevated in activated T cells (6). Via its interactions with endothelial hyaluronan, CD44 functions as a prominent adhesion receptor in autoimmune T cell adhesion on the endothelium and the subsequent transmigration events (7-11). Membrane type-1 matrix metalloproteinase (MT1-MMP) (12, 13) is the most important cell surface-associated proteinase that contributes to the shedding CD44 in the adherent autoimmune CD8 ϩ T cells (11,14). As demonstrated in our earlier cell-based tests (8, 9, 14), MT1-MMP cleavage releases the extracellular domain of CD44 from T cell surfaces and inactivates the CD44 cell receptor function. Similarly, the cleavage of CD44 by MT1-MMP plays a significant role in the regulation of tumor cell migration (15, 16). By means of this regulatory proteolysis, which our earlier data suggest (8, 9, 14), MT1-MMP appears to control the severity of the diabetic disease and mediates the transit...

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In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

Cited by 31 publications

References 67 publications

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

The Importance of Myeloid-Derived Suppressor Cells in the Regulation of Autoimmune Effector Cells by a Chronic Contact Eczema

Specific Inhibition of Autoimmune T Cell Transmigration Contributes to β Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice

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