Regulation of TCR Signaling by CD45 Lacking Transmembrane and Extracellular Domains

Volarević, Siniša; Niklinska, B B; Burns, Christopher M.; June, Carl H.; Weissman, Allan M.; Ashwell, Jonathan D.

doi:10.1126/science.8475386

Cited by 126 publications

(81 citation statements)

References 24 publications

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“…Using CD45-deficient cell lines and CD45 gene-disrupted mice, it has been shown that CD45 functions as an important regulator of maturation and activation pathways in lymphocytes (1)(2)(3). The importance of the phosphatase activity of CD45 in lymphocyte activation has been confirmed by the finding that transfection of chimeric proteins containing the cytoplasmic domains of CD45 into cells deficient in CD45 expression restores normal T cell signaling events (4,5). Downstream substrates of CD45 have been identified as the protein tyrosine kinases p56 lck and p59…”

mentioning

confidence: 67%

Dynamic Association of CD45 with Detergent-Insoluble Microdomains in T Lymphocytes

Edmonds

Ostergaard

2002

The Journal of Immunology

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The receptor-like protein tyrosine phosphatase CD45 is essential for TCR signal transduction. Substrates of CD45 include the protein tyrosine kinases p56lck and p59fyn, both of which have been shown to be enriched in detergent-insoluble microdomains. Here we find that there is a cholesterol-dependent association between CD45 and the raft-associated protein linker for activation of T cells, suggesting that CD45 and linker for activation of T cells may colocalize in lipid rafts. Consistent with this observation, we find that ∼5% of total CD45 can be detected in Triton X-100-insoluble buoyant fractions of sucrose gradients, demonstrating that CD45 is not excluded from lipid rafts. Upon stimulation of T cells with anti-CD3, there is a reduction in the amount of CD45 found associating with lipid rafts. Our data suggest that CD45 is present in lipid rafts in T cells before activation, perhaps to activate raft-associated p56lck, allowing membrane-proximal signaling events to proceed. Furthermore, the reduction in CD45 content of lipid rafts after CD3 stimulation may serve to limit the amounts of activated p56lck in rafts and thus possibly the duration of T cell responses.

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mentioning

confidence: 67%

Dynamic Association of CD45 with Detergent-Insoluble Microdomains in T Lymphocytes

Edmonds

Ostergaard

2002

The Journal of Immunology

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“…Studies of CD45-deficient cell lines and CD45-deficient mice initially demonstrated an essential role for CD45 in TCR-mediated signal transduction as a positive regulator (25,26). However, recently, an unexpected function of CD45 has been reported: CD45 could negatively regulate cytokine receptor signaling (27,28).…”

Section: Discussionmentioning

confidence: 99%

Cross-Linking of CD45 on Suppressive/Regulatory T Cells Leads to the Abrogation of Their Suppressive Activity In Vitro

Shimizu

Iida

Sato³

et al. 2005

The Journal of Immunology

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CD4+CD25+ T cells have immunoregulatory and suppressive functions and are responsible for suppressing self-reactive cells and maintaining self-tolerance. In addition to CD4+CD25+ T cells, there is some evidence that a fraction of CD4+CD25− T cells exhibit suppressive activity in vitro or in vivo. We have shown, using aged mice, that aging not only leads to a decline in the ability to mount CD4+CD25− T cell responses, but, at the same time, renders aged CD4+CD25− T cells suppressive. In this study we report two newly established mAbs that could abrogate the suppressive function of aged CD4+CD25− T cells. These mAbs recognized the same protein, the transmembrane phosphatase CD45. Cross-linking of CD45 on aged CD4+CD25− T cells was required for the disruption of their suppressive activity. Surprisingly, these mAbs also abrogated the suppressive action of CD4+CD25+ T cells in vitro. Our results demonstrate an unexpected function of CD45 as a negative regulator neutralizing the suppressive activity of aged CD4+CD25− and young CD4+CD25+ T cells.

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“…Furthermore, transfection of the cytoplasmic domain of CD45 (containing tyrosine phosphatase activity) into CD45-negative cells was also able to moderately restore the migratory response, suggesting that CD45 phosphatase activity is important for mediating CXCL12-induced chemotactic signaling. The cytoplasmic domain of CD45 has also been shown to be required for TCR-mediated signaling events (22,23).…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45

Fernandis¹,

Cherla²,

Ganju

2003

Journal of Biological Chemistry

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The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1␣ (CXCL12), regulate lymphocyte trafficking and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase (

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Regulation of TCR Signaling by CD45 Lacking Transmembrane and Extracellular Domains

Cited by 126 publications

References 24 publications

Dynamic Association of CD45 with Detergent-Insoluble Microdomains in T Lymphocytes

Dynamic Association of CD45 with Detergent-Insoluble Microdomains in T Lymphocytes

Cross-Linking of CD45 on Suppressive/Regulatory T Cells Leads to the Abrogation of Their Suppressive Activity In Vitro

Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45

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