Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development

Falahati, Rustom; Leitenberg, David

doi:10.4049/jimmunol.178.4.2056

Cited by 21 publications

(15 citation statements)

References 54 publications

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“…Indeed, while constitutive ζ-chain phosphorylation in DP thymocytes has been demonstrated to depend upon non-selecting MHC and Lck, it is coreceptor independent (Becker et al, 2007; van Oers et al, 1996a; van Oers et al, 1993). We propose therefore that independent pools of CD4-associated and ‘free’ Lck may be differentially regulated by CD45 and independently mediate basal and inducible signaling (Falahati and Leitenberg, 2007; Leitenberg et al, 1996). …”

Section: Discussionmentioning

confidence: 99%

CD45-Csk Phosphatase-Kinase Titration Uncouples Basal and Inducible T Cell Receptor Signaling during Thymic Development

et al. 2010

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SUMMARY The kinase-phosphatase pair Csk and CD45 reciprocally regulate phosphorylation of the inhibitory tyrosine of the Src family kinases Lck and Fyn. T cell receptor (TCR) signaling and thymic development require CD45 expression but proceed constitutively in the absence of Csk. Here we show that relative titration of CD45 and Csk expression reveals distinct regulation of basal and inducible TCR signaling during thymic development. Low CD45 expression is sufficient to rescue inducible TCR signaling and positive selection, while high expression is required to reconstitute basal TCR signaling and beta selection. CD45 has a dual positive and negative regulatory role during inducible but not basal TCR signaling. By contrast, Csk plays a positive regulatory role during basal but not inducible signaling. High physiologic expression of CD45 is thus required for two reasons, to down-modulate inducible TCR signaling during positive selection, and to counteract Csk during basal TCR signaling.

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Section: Discussionmentioning

confidence: 99%

CD45-Csk Phosphatase-Kinase Titration Uncouples Basal and Inducible T Cell Receptor Signaling during Thymic Development

et al. 2010

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“…Fyn, which is a less effective CD45 substrate and upregulated during thymic development and in peripheral T cells, could play a critical role in this process, potentially via its interactions with PAG/Cbp (29)(30)(31). Maturation-specific differences in signaling networks could also explain the hyperresponsiveness of DP and SP thymocytes and hyporesponsiveness of peripheral naïve CD4 ϩ T cells to the same stimuli (32,33). A similar dichotomy in T cell responsiveness has been reported in mice expressing c-Cbl mutations, further supporting differences between (or rewiring of) signaling networks in different T cell compartments (34).…”

Section: Discussionmentioning

confidence: 99%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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“…CD45 expression is crucial for T cell development as well as in controlling the threshold of Ag-mediated activation in peripheral T lymphocytes (22,29,39,40). Larger CD45 isoforms (e.g., CD45RABC, -RAB, -RBC, or -RB) facilitate the activation through the TCR, whereas T cells expressing CD45RO need a stronger signal to obtain the same level of activation (27,41).…”

Section: Discussionmentioning

confidence: 99%

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

Gaudreau

Heyd

Bastien

et al. 2012

The Journal of Immunology

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The regulation of posttranscriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development, and immunity. The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. CD45 is known to be alternatively spliced, a process that is partially regulated by heterogeneous nuclear ribonucleoprotein (hnRNP) L. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice and found that LckCre-mediated deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between double-negative 4 and double-positive cells. In addition, hnRNP L−/− thymocytes express aberrant levels of the CD45RA splice isoforms and show high levels of phosphorylated Lck at the activator tyrosine Y394, but lack phosphorylation of the inhibitory tyrosine Y505. This indicated an increased basal Lck activity and correlated with higher proliferation rates of double-negative 4 cells in hnRNP L−/− mice. Deletion of hnRNP L also blocked the migration and egress of single-positive thymocytes to peripheral lymphoid organs in response to sphingosine-1-phosphate and the chemokines CCL21 and CXCL12 very likely as a result of aberrant splicing of genes encoding GTPase regulators and proteins affecting cytoskeletal organization. Our results indicate that hnRNP L regulates T cell differentiation and migration by regulating pre-TCR and chemokine receptor signaling.

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Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development

Cited by 21 publications

References 54 publications

CD45-Csk Phosphatase-Kinase Titration Uncouples Basal and Inducible T Cell Receptor Signaling during Thymic Development

CD45-Csk Phosphatase-Kinase Titration Uncouples Basal and Inducible T Cell Receptor Signaling during Thymic Development

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

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