A role of kinase inactive ZAP-70 in altered peptide ligand stimulated T cell activation

Kim, Jeong Ran; Irie, Atsushi; Tsukamoto, Hirotake; Nishimura, Yasuharu

doi:10.1016/j.bbrc.2005.12.143

Cited by 5 publications

(5 citation statements)

References 32 publications

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“…4B), and NK/ T-CL patients (rs = 0.524, p < 0.05) (Fig. 4C), further supporting the correlation between the TCRf and ZAP-70 genes in T-cell activation for sound and defective cellular immunity (Kim et al, 2006;Fischer et al, 2010). FceRIc TCRf, ZAP-70, AND FCeRIc IN T-AND NK/T-CELL LYMPHOMAfunctions like a candidate for replacing TCRf through its association with Syk, which is regarded to be 100-fold more potent than ZAP-70 and preferentially recruited to the FceRIc receptor (Krishnan et al, 2003).…”

Section: Tcrf Zap-70 and Fceric In T-and Nk/t-cell Lymphomasupporting

confidence: 51%

“…TCRf chain tyrosine phosphorylation is the first step in the signal transduction cascade initiated after TCR/CD3 engagement followed by phosphorylation of the cellular substrate ZAP-70 (TCRf chain-associated protein kinase 70 kDa), a cytosolic protein. The association between a lack of ZAP-70 expression with immunodeficiency consisting of markedly reduced T-cell-mediated immunity highlights the crucial role of this tyrosine kinase in T-cell development and function (Kim et al, 2006;Fischer et al, 2010). The upregulation of FceRIc (Fc epsilon receptor type Ig) expression is observed in peripheral T cells in patients with immunological diseases and T cells that infiltrate tumor sites Li et al, 2012a).…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of TCRζ, ZAP-70, and FcɛRIγ Gene Expression in Patients with T- and NK/T-Cell Lymphoma

Liao

Zhou

Wang

et al. 2015

DNA and Cell Biology

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Section: Tcrf Zap-70 and Fceric In T-and Nk/t-cell Lymphomasupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Characteristics of TCRζ, ZAP-70, and FcɛRIγ Gene Expression in Patients with T- and NK/T-Cell Lymphoma

Liao

Zhou

Wang

et al. 2015

DNA and Cell Biology

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“…Partially agonistic peptides can selectively stimulate some T cell effector functions by inducing a pattern of signal transduction that is qualitatively different from the pattern induced by any concentration of the native peptide (9, 44–46). Partial agonistic signaling patterns are characterized by differential phosphorylation of TCR subunits, recruitment but no activation of ZAP-70, activation of MAP kinases (although for a shortened time period) and/or phenotypically distinct Ca 2+ fluxes (11, 47, 48). A shortened period of MAP kinase activation and/or weakened Ca 2+ flux could explain the observed lack of NFAT activation in T cells following stimulation with S4S6 peptide.…”

Section: Discussionmentioning

confidence: 99%

An Altered gp100 Peptide Ligand with Decreased Binding by TCR and CD8α Dissects T Cell Cytotoxicity from Production of Cytokines and Activation of NFAT

Schaft¹,

Coccoris²,

Drexhage³

et al. 2013

Front. Immunol.

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Altered peptide ligands (APLs) provide useful tools to study T cell activation and potentially direct immune responses to improve treatment of cancer patients. To better understand and exploit APLs, we studied the relationship between APLs and T cell function in more detail. Here, we tested a broad panel of gp100280–288 APLs with respect to T cell cytotoxicity, production of cytokines, and activation of Nuclear Factor of Activated T cells (NFAT) by human T cells gene-engineered with a gp100-HLA-A2-specific TCRαβ. We demonstrated that gp100-specific cytotoxicity, production of cytokines, and activation of NFAT were not affected by APLs with single amino acid substitutions, except for an APL with an amino acid substitution at position 3 (APL A3), which did not elicit any T cell response. A gp100 peptide with a double amino acid mutation (APL S4S6) elicited T cell cytotoxicity and production of IFNγ, and to a lesser extent TNFα, IL-4, and IL-5, but not production of IL-2 and IL-10, or activation of NFAT. Notably, T cell receptor (TCR)-mediated functions showed decreases in sensitivities for S4S6 versus gp100 wild-type (wt) peptide, which were minor for cytotoxicity but at least a 1000-fold more prominent for the production of cytokines. TCR-engineered T cells did not bind A3-HLA-A2, but did bind S4S6-HLA-A2 although to a lowered extent compared to wt peptide-HLA-A2. Moreover, S4S6-induced T cell function demonstrated an enhanced dependency on CD8α. Taken together, most gp100 APLs functioned as agonists, but A3 and S4S6 peptides acted as a null ligand and partial agonist, respectively. Our results further suggest that TCR-mediated cytotoxicity can be dissected from production of cytokines and activation of NFAT, and that the agonist potential of peptide mutants relates to the extent of binding by TCR and CD8α. These findings may facilitate the design of APLs to advance the study of T cell activation and their use for therapeutic applications.

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“…Collectively, we suggest that the extent and rate of accumulation of Raf‐1 or B‐Raf/ERK activation was reflected by the level of TCR stimulation, which was determined by both the antigen dose and the dissociation rate of the TCR‐ligand complex, i.e ., TCR affinity 12, 15, 16, 33. Furthermore, Q59GDR4 stimulation was drastically less efficient in inducting TCR down‐modulation, an index of the productive TCR triggering 34. This might be one possible cause for the sustained B‐Raf/ERK activation in Q59GDR4‐stimulated T cells, since the absence of TCR down‐modulation led to unlimited TCR ligation, and a continuous input of subtle signal through the TCR.…”

Section: Discussionmentioning

confidence: 99%

TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4⁺ T cell clone

et al. 2006

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The interactions between peptide/MHC complexes and their cognate TCR are essential for various T cell responses. However, the relationship between the avidity of TCR ligand and the subsequent intracellular signaling through the TCR is still unclear. To investigate the effects of TCR ligand avidity on TCR-mediated signaling, we established L cells expressing HLA-DR4 molecules covalently linked with agonistic peptide (highaffinity ligand) or altered peptide ligand (APL; low-affinity ligand) at various densities as APC for a cognate human CD4 + T cell clone. Using this system, we demonstrated that the T cell clone stimulated with APL/HLA-DR4 complexes presented at an excessive density provoked the up-regulation of CD69, IL-2 production and proliferation, but no detectable phosphorylation of ZAP-70/LAT/SLP-76. Furthermore, in contrast to the high-affinity stimulation, the low-affinity stimulation evoked delayed and sustained activation of the B-Raf/extracellular signal-regulated kinase (ERK) pathway without Raf-1 activation. The strength and duration of B-Raf/ERK activations closely correlated with the density of the TCR ligand. A knockdown approach confirmed that B-Raf activation was indispensable for the APL-induced T cell responses. These observations suggest that the differences in TCR-peptide/MHC interactions reflect the strength and duration of B-Raf/Raf-1/ERK activation in the human CD4 + T cells.

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A role of kinase inactive ZAP-70 in altered peptide ligand stimulated T cell activation

Cited by 5 publications

References 32 publications

Characteristics of TCRζ, ZAP-70, and FcɛRIγ Gene Expression in Patients with T- and NK/T-Cell Lymphoma

Characteristics of TCRζ, ZAP-70, and FcɛRIγ Gene Expression in Patients with T- and NK/T-Cell Lymphoma

An Altered gp100 Peptide Ligand with Decreased Binding by TCR and CD8α Dissects T Cell Cytotoxicity from Production of Cytokines and Activation of NFAT

TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4⁺ T cell clone

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A role of kinase inactive ZAP-70 in altered peptide ligand stimulated T cell activation

Cited by 5 publications

References 32 publications

Characteristics of TCRζ, ZAP-70, and FcɛRIγ Gene Expression in Patients with T- and NK/T-Cell Lymphoma

Characteristics of TCRζ, ZAP-70, and FcɛRIγ Gene Expression in Patients with T- and NK/T-Cell Lymphoma

An Altered gp100 Peptide Ligand with Decreased Binding by TCR and CD8α Dissects T Cell Cytotoxicity from Production of Cytokines and Activation of NFAT

TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4+ T cell clone

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TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4⁺ T cell clone