Involvement of CD4 D3–D4 membrane proximal extracellular domain for the inhibitory effect of oxidative stress on activation-induced CD4 down-regulation and its possible role for T cell activation

Nakamura, Kazuhiro; Yube, Kouichi; Miyatake, Akira; Cambier, John C.; Hirashima, Mitsuomi

doi:10.1016/s0161-5890(03)00030-0

Cited by 14 publications

(10 citation statements)

References 64 publications

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“…It has been well documented that Lck phosphorylation can be induced by activated Fcγ R (37,38). The current study indicates that Lck is highly phosphorylated in HSCs and the phosphorylation of Lck does not depend on the addition of intact IgG.…”

Section: Discussionsupporting

confidence: 59%

Expression of Fc Fragment Receptors of Immunoglobulin G (Fc?Rs) in Rat Hepatic Stellate Cells

et al. 2005

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Hepatic stellate cells (HSCs) are now considered the major cell type in the liver mediating the development of liver fibrosis. Recently it was demonstrated that HSCs express membrane proteins involved in antigen presentation. We further evaluate immunological properties of HSCs by examining the expression and function of the Fc fragment of immunoglobulin G (IgG) in HSCs. In this study, we document the presence of mRNAs for three Fc gammaRs in HSCs. Ligand binding assay indicated the existence of Fc gammaRs with different binding affinities on membranes of HSCs. We also documented that the abundance of the three Fc gammaR mRNAs increased upon activation of HSCs in vitro. Moreover, an examination of the biological activities of IgG revealed that exposure to IgG significantly stimulated HSC differentiation and proliferation. Furthermore, we studied the intracellular signaling protein, LcK, in HSCs and regulation of Lck expression and phosphorylation by IgG. Although IgG did not regulate Lck abundance and phosphorylation in HSCs, highly phosphorylated Lck was present in these cells. In conclusion, we provided evidence that HSCs expresses receptors for the Fc fragment of IgG, and IgG regulates HSC differentiation and proliferation. Therefore, immunoglobulin G may play a role in HSC activation.

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Section: Discussionsupporting

confidence: 59%

Expression of Fc Fragment Receptors of Immunoglobulin G (Fc?Rs) in Rat Hepatic Stellate Cells

et al. 2005

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“…MDSC also replenish the tumor stroma with precursors of both TAM and TAN which contribute to oxidative stress in the TME (27). The multifaceted impact of oxidative stress in the TME is reflected not only in the impairment of T cell and NK cell activity, but also on redox mediated regulation of T cell signaling and T cell survival (22, 28). The differentiation state of the lymphocytes determines their function and persistence (29, 30).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that redox regulation by MDSC may cause an intrinsic defect in the ability of T EM and T CM to proliferate in response to tumor challenge and this defect could be reversed or rectified by depletion of MDSC and associated ROS in the TME. Oxidative stress in the TME may also affect the differentiation pathways of these memory subsets and skew the memory repertoire toward subsets that are less sensitive to oxidative stress such as the T CM and T EM 22, 28). Depletion of ROS and MDSC from TME could then trigger the expansion of these resistant memory cell subsets, as well as T SCM (stem cell phenotype with high proliferative capacity).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Antitumor Immunity in Lung Cancer by Targeting Myeloid-Derived Suppressor Cell Pathways

et al. 2013

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Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of frontline therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term anti-tumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective anti-tumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8+ T cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8+ T cell response and further decreased T regulatory cell infiltration. For long-term anti-tumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively-transferred memory cells responded to tumor re-challenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, generate effector and persistent memory cells for tumor eradication, and prevent lung cancer relapse.

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“…Scatter was increased in cultures containing RetCD45 cells activated with the combination of IFN-␥ and anti-CD40. The expression level of CD4 on T cells is known to be decreased upon activation by Ag/APC (37), cross-linking of TCR (38), beadbound peptide/MHC (39), and PMA (37). In preliminary studies, we found that expression of CD4 decreases upon activation via the TCR of AE-T cells, providing another measure of T cell activation resulting from APC activity (data not shown).…”

Section: Activated Retcd45 Cells Show Increased Ability To Present Agmentioning

confidence: 99%

The Antigen-Presenting Activity of Fresh, Adult Parenchymal Microglia and Perivascular Cells from Retina

Gregerson

Sam

McPherson

2004

The Journal of Immunology

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Although several observations show local T cell recognition of retinal Ag, there has been no direct demonstration that the APC were retinal derived, rather than recruited. In this study, CD45+ cells isolated from immunologically quiescent murine retina were tested in vitro for functional evidence of Ag presentation to naive and Ag-experienced CD4 T cells specific for β-galactosidase. Because CD45+ cells from brain have been reported to be efficient APC, they were included for comparison. Measures of activation included changes in CD4, CD25, CD44, CD45RB, CD62L, CD69, caspase-3 activation, CFSE dilution, size, number of cells recovered, and cytokine production. Retinal CD45+ cells gave no evidence of Ag-dependent TCR ligation in naive T cells, unlike splenic APC and CD45+ cells from brain, which supported potent responses. Instead, addition of retinal CD45+ cells to cocultures of naive 3E9 T cells plus splenic APC reduced the yield of activated T cells and cytokine production by limiting T cell activation at early time points. Ag-experienced T cells responded weakly to Ag presented by retinal CD45+ cells. Activating the retinal cells with IFN-γ, anti-CD40, or LPS incrementally increased their APC activity. Addition of neutralizing Abs to TGF-β did not reveal suppressed retinal APC activity. Because retina lacks tissue equivalents of meninges and choroid plexus, rich sources of dendritic cells in brain, cells from retina may better represent the APC activity of fresh, adult CNS parenchymal and perivascular cells. The activity of the retinal CD45+ cells appears to be directed to limiting T cell responses.

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Involvement of CD4 D3–D4 membrane proximal extracellular domain for the inhibitory effect of oxidative stress on activation-induced CD4 down-regulation and its possible role for T cell activation

Cited by 14 publications

References 64 publications

Expression of Fc Fragment Receptors of Immunoglobulin G (Fc?Rs) in Rat Hepatic Stellate Cells

Expression of Fc Fragment Receptors of Immunoglobulin G (Fc?Rs) in Rat Hepatic Stellate Cells

Enhancement of Antitumor Immunity in Lung Cancer by Targeting Myeloid-Derived Suppressor Cell Pathways

The Antigen-Presenting Activity of Fresh, Adult Parenchymal Microglia and Perivascular Cells from Retina

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