Function of CD44(Pgp-1) homing receptor in human T cell precursors

Hera, Alberto De La; Acevedo, Agustín; Marston, Wendy L.; Sánchez‐Madrid, Francisco

doi:10.1093/intimm/1.6.598

Cited by 20 publications

(13 citation statements)

References 30 publications

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“…In the thymus, laminin-5-induced CD44 cleavage by metalloproteinase-14 also directs the migration of mature thymocytes within the medulla as well as the exit from the medulla (34). The rare population of uncommitted CD44 dim ETPs is present in subcapsular clusters in the cortex of the thymus, suggesting that CD44 also directs thymocyte precursors from the bone marrow to the thymus, entry into the thymus, and potentially intrathymic migration during early T-cell development (35, 36). …”

Section: Discussionmentioning

confidence: 99%

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

Canté-Barrett

Mendes

et al. 2017

Front. Immunol.

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Human T-cell development is less well studied than its murine counterpart due to the lack of genetic tools and the difficulty of obtaining cells and tissues. Here, we report the transcriptional landscape of 11 immature, consecutive human T-cell developmental stages. The changes in gene expression of cultured stem cells on OP9-DL1 match those of ex vivo isolated murine and human thymocytes. These analyses led us to define evolutionary conserved gene signatures that represent pre- and post-αβ T-cell commitment stages. We found that loss of dim expression of CD44 marks human T-cell commitment in early CD7+CD5+CD45dim cells, before the acquisition of CD1a surface expression. The CD44−CD1a− post-committed thymocytes have initiated in frame T-cell receptor rearrangements that are accompanied by loss of capacity to differentiate toward myeloid, B- and NK-lineages, unlike uncommitted CD44dimCD1a− thymocytes. Therefore, loss of CD44 represents a previously unrecognized human thymocyte stage that defines the earliest committed T-cell population in the thymus.

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Section: Discussionmentioning

confidence: 99%

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

Canté-Barrett

Mendes

et al. 2017

Front. Immunol.

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“…CD44 plays a crucial role in inflammation [49] and in cancer progression [50]. It is also involved in leukocyte recruitment [51] and regulates T cell interactions during T cell development [52]. Since CD44 exists in many isoforms and is extensively spliced [53], MARCH-VIII dependent down-regulation might be variant-specific.…”

Section: Discussionmentioning

confidence: 99%

Membrane-Associated RING-CH Proteins Associate with Bap31 and Target CD81 and CD44 to Lysosomes

et al. 2010

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Membrane-associated RING-CH (MARCH) proteins represent a family of transmembrane ubiquitin ligases modulating intracellular trafficking and turnover of transmembrane protein targets. While homologous proteins encoded by gamma-2 herpesviruses and leporipoxviruses have been studied extensively, limited information is available regarding the physiological targets of cellular MARCH proteins. To identify host cell proteins targeted by the human MARCH-VIII ubiquitin ligase we used stable isotope labeling of amino-acids in cell culture (SILAC) to monitor MARCH-dependent changes in the membrane proteomes of human fibroblasts. Unexpectedly, we observed that MARCH-VIII reduced the surface expression of Bap31, a chaperone that predominantly resides in the endoplasmic reticulum (ER). We demonstrate that Bap31 associates with the transmembrane domains of several MARCH proteins and controls intracellular transport of MARCH proteins. In addition, we observed that MARCH-VIII reduced the surface expression of the hyaluronic acid-receptor CD44 and both MARCH-VIII and MARCH-IV sequestered the tetraspanin CD81 in endo-lysosomal vesicles. Moreover, gene knockdown of MARCH-IV increased surface levels of endogenous CD81 suggesting a constitutive involvement of this family of ubiquitin ligases in the turnover of tetraspanins. Our data thus suggest a role of MARCH-VIII and MARCH-IV in the regulated turnover of CD81 and CD44, two ubiquitously expressed, multifunctional proteins.

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“…The participation of CD44 in BM engraftment was confirmed in a therapeutic assay wherein Rag2 -/-× γc -/mice transplanted with untreated ICN1-transduced ETPs were subjected to serial i.p. administration of the blocking anti-CD44 mAb HP2/9 (IgG1) (28,29), starting at day 5 after transplant ( Figure 6B), when ETPs have already seeded the host BM ( Figure 2F and data not shown). We found a significant reduction (>100-fold) of ICN1 + T cell ectopic generation and expansion in anti-CD44-treated…”

Section: Cd44 Is a Direct Transcriptional Target Of Notch1 In T-all Cmentioning

confidence: 99%

The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model

García-Peydró

Fuentes

Mosquera

et al. 2018

Journal of Clinical Investigation

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NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.

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Function of CD44(Pgp-1) homing receptor in human T cell precursors

Cited by 20 publications

References 30 publications

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

Membrane-Associated RING-CH Proteins Associate with Bap31 and Target CD81 and CD44 to Lysosomes

The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model

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