Downstream of Tyrosine Kinases-1 and Src Homology 2-Containing Inositol 5′-Phosphatase Are Required for Regulation of CD4+CD25+ T Cell Development

Kashiwada, Masaki; Cattoretti, Giorgio; McKeag, Lisa; Rouse, Todd; Showalter, Brian M.; Al-Alem, Umaima; Niki, Masaru; Pandolfi, Pier Paolo; Field, Elizabeth H.; Rothman, Paul B.

doi:10.4049/jimmunol.176.7.3958

Cited by 57 publications

(73 citation statements)

References 47 publications

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“…Flowcytometric analysis of the thymus and peripheral tissues revealed normal percentage of T cell populations in mice with T cell-specific deletion of SHIP (SI Table 1). Mice with germ-line deletion of SHIP were shown to have an increased number of regulatory T cells (23). The number of regulatory T cells in CD4cre SHIP fl/fl mice, judged by the percentage of FoxP3 ϩ cells in spleen, was similar to that of wild-type mice (SI Table 1).…”

Section: Resultsmentioning

confidence: 79%

“…From the analysis of SHIP-null mice, Kashiwada et al (23) reported that full expression of the inositol phosphatase SHIP was necessary to restrict the development of regulatory T cells. However, considering the highly pleiotropic phenotype of SHIP-null mice, it is difficult to evaluate whether there is a T cell-intrinsic role of SHIP in T cell development and function.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, SHIP does not appear to have a significant impact on T cell development. Peripheral T cells from SHIP-null mice have been shown to be constitutively activated and to give rise to increased numbers of CD4 ϩ CD25 ϩ regulatory T cells (23). However, given that SHIP-null mice develop severe myeloproliferative disease, it is unclear whether the differences observed in T cell function are due to a T cell-intrinsic role of SHIP or are simply the consequences of the inflammatory environment brought about by SHIP-deficient myeloid cells.…”

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confidence: 99%

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T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

Тарасенко

Kole

Anthony

et al. 2007

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

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The 5 -phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient T cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8 ؉ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity.cytotoxicity ͉ T-bet T he 5Ј-inositol phosphatase SHIP is a well characterized inhibitory molecule that regulates cell responses in lymphocytes and myeloid cells by its ability to hydrolyze the second messenger PI(3,4,5) trisphosphate (1-4). SHIP is recruited by engagement of the inhibitory Fc receptor in B cells and mast cells (5)(6)(7)(8) or by the engagement of FcRs (Fc RI and Fc␥RIII), cytokine [interleukin 3 (IL3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGF␤], and growth factor (steel factor and M-CSF) receptors in myeloid cells (2, 9). Once SHIP is recruited to the membrane by the signaling complexes, its enzymatic activity depletes PI(3,4,5)P 3 and prevents membrane localization of PHdomain-containing factors such as Tec kinases, Akt, and PLC␥ (10-13). This inhibitory effect ultimately leads to reduced calcium influx and prevents cellular activation (14).Germ-line deletion of SHIP in mice leads to early mortality from a myeloproliferative-like syndrome characterized by profound splenomegaly and massive myeloid infiltration of the lung (15). B cells develop abnormally in SHIP-null mice, with an activated phenotype and specifically lacking the marginal zone B cell population (16,17). The absence of marginal-zone B cells in SHIP-null mice has been explained not as a B cell primary defect, but as a consequence of macrophage dysregulation in the spleen of these animals (17). Macrophages from SHIP-null mice are skewed toward an M2-activated phenotype showing high levels of arginase I (ArgI) and Ym1. R...

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Section: Resultsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

Тарасенко

Kole

Anthony

et al. 2007

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

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“…Closer analysis of peripheral T cells from SHIP-null mice reveals that they are constitutively activated and give rise to increased numbers of CD4 ϩ CD25 ϩ T Reg cells, suggesting a key regulatory role for SHIP in T Reg cell development (36). However, this may be a consequence of the inflammatory environment brought about by SHIP-deficient myeloid cells rather than a T cell defect per se.…”

Section: Insights Into the Role Of Ship In T Lymphocytes From Gene Tamentioning

confidence: 99%

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Harris

Parry

Westwick

et al. 2008

Journal of Biological Chemistry

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The phosphoinositide 3-kinase signaling pathway has been implicated in a range of T lymphocyte cellular functions, particularly growth, proliferation, cytokine secretion, and survival. Dysregulation of phosphoinositide 3-kinase-dependent signaling and function in leukocytes, including B and T lymphocytes, has been implicated in many inflammatory and autoimmune diseases. As befits a pivotal signaling cascade, several mechanisms exist to ensure that the pathway is tightly regulated. This minireview focuses on two lipid phosphatases, viz. the 3 -phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SHIP (Src homology 2 domain-containing inositol-5-phosphatase). We discuss their role in regulating T lymphocyte signaling as well their potential as future therapeutic targets.The PI3K 3 pathway plays a central role in regulating many biological processes, primarily via the generation of the potent second messenger PtdIns(3,4,5)P 3 , which acts as a docking site at the plasma membrane, recruiting and activating proteins containing pleckstrin homology (PH) domains (1). These downstream PI3K effectors include PDK-1 (3Ј-phosphoinositide-dependent kinase-1), which phosphorylates and activates the AGC protein kinases, including protein kinase B/Akt. Other kinases such as Tec family kinases can also interact directly with PtdIns(3,4,5)P 3 , as can GTPase-activating proteins and guanine nucleotide exchange factors as well as scaffolding proteins that nucleate the assembly of key signaling complexes (1, 2). PI3K and T LymphocytesT cells express all three class 1A PI3K isoforms (p110␣, p110␤, and p110␦), which are regulated by protein-tyrosine kinase-coupled receptors, as well as class 1B p110␥, which is activated by G protein-coupled receptors (GPCRs). The T cell antigen receptor (TCR), CD28 family co-stimulatory receptors, and cytokine receptors activate class 1A isoforms (3). Chemokines (by virtue of interacting with GPCRs), activate mainly class 1B PI3K (4). Use of pharmacological tools in leukemic human T cell lines first indicated a possible role for PI3K in T cell activation (5). Mice with a knock-in point mutation of p110␦ that abolishes kinase activity exhibit selective impairments in TCR signaling and reduced proliferation in vitro (6) and impaired function of CD4 ϩ CD25 ϩ Foxp3 ϩ T Reg cells (7). Interestingly, mice lacking both p110␥ and p110␦ show much more profound defects in thymocyte development and survival compared with mice lacking individual isoforms, indicating that these isoforms serve partially redundant functions in thymocytes (8, 9). Pathological consequences of combined p110␥␦ deficiency includes T cell lymphopenia, which leads to multiple-organ inflammation (10). Surprisingly, mice with T cellspecific loss of class 1A PI3K exhibit largely normal thymocyte development, and peripheral T cell numbers and subsets are unimpaired in young animals (11,12). In vitro proliferation of T cells from these mice in response to TCR ligation is abrogated, and there is complete loss of PI3K sig...

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“…The overexpression of Dok-2 in bone marrow cells selectively inhibited early maturation of thymocytes from the DN to DP stage [28]. In addition, Dok-1 has been shown to cooperate with SHIP in the regulation of T-cell development since the combined loss of Dok-1 and SHIP expression led to a severe reduction in thymocyte numbers [37].In this study, we investigated the involvement of Dok in the regulation of T-cell development. To this end, we generated transgenic mice overexpressing Dok-1 under the control of the CD2 promoter leading to transgene expression in thymocytes and mature T cells.…”

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confidence: 99%

Dok‐1 overexpression promotes development of γδ natural killer T cells

et al. 2012

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In T cells, two members of the Dok family, Dok-1 and Dok-2, are predominantly expressed. Recent evidence suggests that they play a negative role in T-cell signaling. In order to define whether Dok proteins regulate T-cell development, we have generated transgenic mice overexpressing Dok-1 in thymocytes and peripheral T cells. We show that overexpression of Dok-1 retards the transition from the CD4 − CD8 − to CD4 + CD8 + stage. Moreover, there is a specific expansion of PLZF-expressing Vγ1.1 + Vδ6.3 + T cells. This subset of γδ T cells acquires innate characteristics including rapid IL-4 production following stimulation and requiring SLAM-associated adaptor protein (SAP) for their development. Moreover, Dok-1 overexpression promotes the generation of an innate-like CD8 + T-cell population that expresses Eomesodermin. Altogether, these findings identify a novel role for Dok-1 in the regulation of thymic differentiation and in particular, in the development of PLZF + γδ T cells.Keywords: γδ T cell r Dok r PLZF r SAP r Thymocyte development Supporting Information available online Introduction αβ T-lymphocyte development is dependent on productive rearrangement of the TCRβ locus and intracellular signaling initiated through the pre-TCR at the CD4 − CD8 − double-negative (DN) stage. Pre-TCR signaling leads to cellular proliferation and progression to the CD4 + CD8 + double-positive (DP) stage where TCRα locus rearrangement is induced. In DP thymocytes, initial TCR signal strength/duration will determine specific gene expression and Correspondence: Dr. Pascale Duplay e-mail: pascale.duplay@iaf.inrs.ca as a consequence will regulate the outcome of thymocyte positive versus negative selection and CD4 versus CD8 lineage differentiation or conventional versus innate lymphocyte lineage choice [1].γδ TCR lymphocytes also develop in the thymus and require productive rearrangement of the TCRγ and δ loci at the DN stage. The strength of TCR signaling is important in controlling αβ/γδ lineage choice. Strong TCR signaling is required for the commitment to the γδ lineage whereas weak TCR signals favor * These authors contributed equally to this work. Eur. J. Immunol. 2012Immunol. . 42: 2491Immunol. -2504 development of αβ lineage cells (reviewed in [2][3][4]). Moreover, TCR signal strength regulates also maturation and acquisition of effector functions in γδ and αβ T-cell development. Therefore, signaling molecules that modulate TCR signal strength play a pivotal role in the regulation of T-cell development and homeostasis. Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as , LAT [10], Grb2 [11], and Gads [12].Dok are adaptor proteins that contain a pleckstrin homology domain, a phosphotyrosine binding domain, and a COOHterminal region containing multiple tyrosine phosphorylation sites [13,14]. Dok-1 and Dok-2, the two members of Dok family proteins e...

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Downstream of Tyrosine Kinases-1 and Src Homology 2-Containing Inositol 5′-Phosphatase Are Required for Regulation of CD4+CD25+ T Cell Development

Cited by 57 publications

References 47 publications

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Dok‐1 overexpression promotes development of γδ natural killer T cells

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