Loss of Src Homology Region 2 Domain-Containing Protein Tyrosine Phosphatase-1 Increases CD8+ T Cell-APC Conjugate Formation and Is Associated with Enhanced In Vivo CTL Function

Sathish, Jean G.; Dolton, Garry; LeRoy, Frances; Matthews, R. James

doi:10.4049/jimmunol.178.1.330

Cited by 26 publications

(26 citation statements)

References 48 publications

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“…SHP-1 has also been implicated in the regulation of the Ras/MAPK pathway. Loss of SHP-1 enhances CTL function and increases the formation of CD8 + T cell-APC contact [58]. In addition to its direct effects on TCR signaling, SHP-1 can associate with the suppressive coregulatory molecule programmed death 1 molecule (PD-1, CD279), which also inhibits T cell activation [59].…”

Section: Role Of Signaling Molecules In T Cell Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Section: Role Of Signaling Molecules In T Cell Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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“…PTPs are critical regulators of signal transduction in lymphocytes and more than 100 PTPs have been reported to date (Marengere et al, 1996;Frearson and Alexander, 1998;Sathish et al, 2007). However, the role of PTPs in macrophages and IL-12 regulation by PTPs still remains largely unknown.…”

Section: Discussionmentioning

confidence: 98%

Enhanced IL-12p40 production by phenylarsine oxide is mediated by cAMP response element in macrophages

et al. 2010

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Phenylarsine oxide (PAO), a membrane-permeable trivalent arsenical, is widely used as an inhibitor of protein tyrosine phosphatases. It reacts with vicinal sulfhydryl groups of proteins to form stable ring structures. Here we show the regulatory function of PAO in immune responses from macrophages. PAO significantly induced the secretion of interleukin (IL)-12p40 in lipopolysaccharide-stimulated macrophages. The mRNA expression and the gene promoter activity of IL-12p40 were enhanced by PAO. These results suggest that PAO may enhance IL-12p40 production at the transcriptional level. Furthermore, the effects of PAO on several signaling molecules regulating IL-12p40 expression were investigated. PAO attenuated the induced binding activity of cAMP response element (CRE), but not of NF-kappaB. Moreover, CRE promoter activity was dose-dependently inhibited by PAO and the increased secretion of IL-12p40 by PAO was reduced by forskolin, a cAMP activator. These results suggest that PAO enhances IL-12p40 production by inhibiting CRE activity.

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“…In this regard, the duration of a stable T cell-APC interaction is critical for determining whether a T cell is to be activated or deleted (30,31). SHP-1-deficient T cells have been shown to be more capable of forming stable conjugates with APCs than normal T cells (32). However, the role of SHP-1 in the regulation of T cell adhesion remains unclear.…”

Section: Discussionmentioning

confidence: 99%

SHP-1 Acts as a Key Regulator of Alloresponses by Modulating LFA-1-Mediated Adhesion in Primary Murine T Cells

Sauer

Herbst

Diekmann

et al. 2016

Molecular and Cellular Biology

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cThe clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft-versus-host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed for the activation of integrins such as LFA-1 is poorly understood. Here, we identified a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting. Upon alloactivation, SHP-1 activity is reduced, resulting in an increase in LFA-1 adhesion compared to that for syngeneically activated T cells. The importance of these differential activation properties was further indicated by small interfering RNA ( R ecipient-derived antigen-presenting cells (APCs) are pivotal for the induction of alloresponses (1). In patients, alloresponses cause significant treatment-related morbidity and mortality, such as graft-versus-host disease (GVHD) or graft rejection. Alloreactive T cells are largely responsible for these detrimental effects (2). In this context, T cell function depends on integrinmediated adhesion and migration.The ␤2 integrins are preferentially expressed among the 12 integrins on lymphocytes. Of these, ␣L␤2 (leukocyte functionassociated antigen 1 [LFA-1], also termed CD11a [␣L chain of LFA-1]-CD18 [␤2 chain of LFA-1]) binds to the ligands ICAM-1, -2, and -3 (intracellular adhesion molecules 1, 2, and 3). The ligands ICAM-1 and -2 are expressed on endothelial cells that line blood vessels on the surface of APCs (3). Following the initial adhesive interaction between potentially alloreactive T cells and allogeneic APCs such as dendritic cells (DCs), LFA-1 facilitates the stable formation of the "immunological synapse," which enhances T cell activation and subsequent effector functions (4, 5). Hence, LFA-1 has emerged as an attractive therapeutic target for the treatment of various inflammatory diseases (6). Immunosuppressive effects induced by LFA-1 antagonists are of substantial interest, since ligation of a T cell receptor (TCR) generates intracellular signals leading to activation of LFA-1-mediated cell adhesion, a process termed "inside-out" signaling. So far, the molecular processes underlying the signaling events between TCR activation and LFA-1 clustering are not fully understood. Adaptor proteins such as ADAP have been identified as key molecules in the TCR "inside-out" pathway (7), and their potential influence in T cell alloreactivity has been discussed (8).Here, we identified the protein tyrosine phosphatase (PTP) SHP-1 as a key regulator of LFA-1-mediated adhesion in primary murine T cells, with particular involvement in alloactivation. We demonstrate for the first time in vitro and in vivo that SHP-1 activity is significantly reduced upon alloactivation, resulting in an increase in the allogeneic activation of T cells and their adhesion to major histocompatibility complex (MHC)-mismatched APCs. Furthermore, we found that SHP-1 ex...

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Loss of Src Homology Region 2 Domain-Containing Protein Tyrosine Phosphatase-1 Increases CD8+ T Cell-APC Conjugate Formation and Is Associated with Enhanced In Vivo CTL Function

Cited by 26 publications

References 48 publications

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Enhanced IL-12p40 production by phenylarsine oxide is mediated by cAMP response element in macrophages

SHP-1 Acts as a Key Regulator of Alloresponses by Modulating LFA-1-Mediated Adhesion in Primary Murine T Cells

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