A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation

Involvement of the Wiskott-Aldrich syndrome protein (WASp) in promoting cell activation requires its release from autoinhibitory structural constraints and has been attributed to WASp association with activated cdc42. Here, however, we show that T cell development and T cell receptor (TCR)-induced proliferation and actin polymerization proceed normally in WASp−/− mice expressing a WASp transgene lacking the cdc42 binding domain. By contrast, mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. These observations identify key roles for Fyn and PTP-PEST in regulating WASp and imply that inducible WASp tyrosine phosphorylation can occur independently of cdc42 binding, but unlike the cdc42 interaction, is absolutely required for WASp contributions to T cell activation.

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Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Journal of Experimental Medicine ◽

10.1084/jem.20112741 ◽

2012 ◽

Vol 209 (6) ◽

pp. 1201-1217 ◽

Cited By ~ 442

Author(s):

Tadashi Yokosuka ◽

Masako Takamatsu ◽

Wakana Kobayashi-Imanishi ◽

Akiko Hashimoto-Tane ◽

Miyuki Azuma ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Activation ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Cell Receptor ◽

Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

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Robust T-cell signaling triggered on soft polydimethylsiloxane-supported lipid-bilayers

10.1101/2020.06.05.134684 ◽

2020 ◽

Author(s):

Anna H. Lippert ◽

Ivan B. Dimov ◽

Alexander Winkel ◽

James McColl ◽

Jane Humphrey ◽

...

Keyword(s):

T Cell ◽

Lipid Bilayers ◽

T Cell Activation ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Supported Lipid Bilayers ◽

Cell Contact ◽

Mechanical Resistance ◽

Cell Contacts ◽

Cell Cell

AbstractThe T-cell receptor (TCR) is thought to be triggered either by mechano-transduction or local tyrosine phosphatase exclusion at cell-cell contacts. However, the effects of the mechanical properties of activating surfaces have only been tested for late-stage T-cell activation, and phosphatase segregation has mostly been studied on glass-supported lipid bilayers that favor imaging but are orders-of-magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing ‘soft bilayers’ with physiological levels of mechanical resistance (Young’s modulus of 4 kPa). Comparisons of T-cell behavior on soft and glass-supported bilayers revealed that early calcium signaling is unaffected by substrate rigidity, implying that early steps in TCR triggering are not mechanosensitive. Robust phosphatase exclusion was observed on the soft bilayers, however, suggesting it likely occurs at cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.

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Negative Regulation of T Cell Activation by Placental Protein 14 Is Mediated by the Tyrosine Phosphatase Receptor CD45

Journal of Biological Chemistry ◽

10.1074/jbc.m211716200 ◽

2003 ◽

Vol 278 (16) ◽

pp. 14059-14065 ◽

Cited By ~ 34

Author(s):

Jacob Rachmilewitz ◽

Zipora Borovsky ◽

Gregory J. Riely ◽

Robin Miller ◽

Mark L. Tykocinski

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Negative Regulation ◽

Placental Protein 14 ◽

Placental Protein

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Expression of CD45 Lacking the Catalytic Protein Tyrosine Phosphatase Domain Modulates Lck Phosphorylation and T Cell Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m413265200 ◽

2005 ◽

Vol 280 (14) ◽

pp. 14318-14324 ◽

Cited By ~ 12

Author(s):

Yanni Wang ◽

Pauline Johnson

Keyword(s):

T Cell ◽

T Cell Activation ◽

Protein Tyrosine Phosphatase ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Phosphatase Domain ◽

Protein Tyrosine

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HLA, CTLA-4 and PTPN22: the shared genetic master-key to autoimmunity?

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399405009981 ◽

2005 ◽

Vol 7 (23) ◽

pp. 1-15 ◽

Cited By ~ 60

Author(s):

Oliver Brand ◽

Stephen Gough ◽

Joanne Heward

Keyword(s):

T Cell ◽

Autoimmune Disease ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Tyrosine Phosphatase ◽

Disease Process ◽

Human Leukocyte ◽

General Effect ◽

Gene Encoding

Several genetic loci appear to be involved in susceptibility to autoimmune disease. Some loci are disease specific, whereas others appear to exert a general effect on the autoimmune disease process. Despite a large number of studies of many different diseases, consistent associations with multiple autoimmune disorders have been restricted to three gene regions: the human leukocyte antigen (HLA) class II region on chromosome 6p21, the gene encoding cytotoxic T lymphocyte-associated 4 (CTLA-4) on chromosome 2q33, and the PTPN22 gene encoding lymphoid tyrosine phosphatase (LYP) on chromosome 1p13. Each of these loci is likely to encode molecules that are crucial in the immune cascade and are actively involved in T-cell activation. Moreover, gene polymorphisms that affect function might contribute to the triggering of autoimmune disease by as-yet-unknown mechanisms. This review summarises recent developments and current understanding of the way in which molecules encoded by these susceptibility loci contribute to T-cell activation, and hypothesises how aberrant function of these molecules might trigger autoimmunity.

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