T-cell activation through the antigen receptor. Part 2: Role of signaling cascades in T-cell differentiation, anergy, immune senescence, and development of immunotherapy

Nel, André E.; Slaughter, Ndaisha

doi:10.1067/mai.2002.124965

Cited by 85 publications

(61 citation statements)

References 121 publications

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“…This central role may be explained by the fact that calcium signals have a pivotal role in the differentiation of specific T cell lineages. Sustained calcium influx is associated with Th1 differentiation, whereas transient influx directs differentiation to the Th2 lineage (50). The rapid inactivation of the ␣7 nAChR is consistent with this theory (42).…”

Section: Discussionsupporting

confidence: 70%

Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

Nizri

Irony-Tur-Sinai

Lory

et al. 2009

The Journal of Immunology

250

230

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The α7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of α7 nAChR activation by nicotine. Our results indicate that the α7 nAChR is expressed on the surface of CD4+ T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-α and IFN-γ) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, α7−/−-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-κB-mediated transcription as measured by IL-2 and IκB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis. α7−/− mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4+ and CD11b+ cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the α7 nAChR in immune modulation and suggest that α7 nAChR agonists may be effective in the treatment of inflammatory disorders.

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Section: Discussionsupporting

confidence: 70%

Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

Nizri

Irony-Tur-Sinai

Lory

et al. 2009

The Journal of Immunology

250

230

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“…In most resting cells, NF-κB is sequestered in the cytoplasm bound to its inhibitor IκB. Upon CD3/CD28 stimulation there is a cascade of tyrosine phosphorylation of various signaling and adapter proteins [68,69] that results in the ubiquitination and degradation of IκB (Fig. 3).…”

Section: Transcription Factor Translocation As An Indicator Of T Cellmentioning

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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“…These kinases phosphorylate the ITAM motifs in CD3 and TCR, enabling binding of ZAP70 (-chain TCR-associated protein kinase 70 kDa), which subsequently phosphorylates linker of activated T cell adaptor protein (LAT). Phosphorylated LAT provides a docking site for an array of proteins involved in TCR signaling (5,6). Although Fyn and Lck are closely related, each is predicted to exert discrete, unique functions (7).…”

Section: The Src Kinase Family Members P56mentioning

confidence: 99%

Lck-Dependent Tyrosine Phosphorylation of Diacylglycerol Kinase α Regulates Its Membrane Association in T Cells

Merino

Ávila-Flores

Shirai³

et al. 2008

The Journal of Immunology

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TCR engagement triggers phospholipase Cγ1 activation through the Lck-ZAP70-linker of activated T cell adaptor protein pathway. This leads to generation of diacylglycerol (DAG) and mobilization of intracellular Ca2+, both essential for TCR-dependent transcriptional responses. TCR ligation also elicits transient recruitment of DAG kinase α (DGKα) to the lymphocyte plasma membrane to phosphorylate DAG, facilitating termination of DAG-regulated signals. The precise mechanisms governing dynamic recruitment of DGKα to the membrane have not been fully elucidated, although Ca2+ influx and tyrosine kinase activation were proposed to be required. We show that DGKα is tyrosine phosphorylated, and identify tyrosine 335 (Y335), at the hinge between the atypical C1 domains and the catalytic region, as essential for membrane localization. Generation of an Ab that recognizes phosphorylated Y335 demonstrates Lck-dependent phosphorylation of endogenous DGKα during TCR activation and shows that pY335DGKα is a minor pool located exclusively at the plasma membrane. Our results identify Y335 as a residue critical for DGKα function and suggest a mechanism by which Lck-dependent phosphorylation and Ca2+ elevation regulate DGKα membrane localization. The concerted action of these two signals results in transient, receptor-regulated DGKα relocalization to the site at which it exerts its function as a negative modulator of DAG-dependent signals.

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T-cell activation through the antigen receptor. Part 2: Role of signaling cascades in T-cell differentiation, anergy, immune senescence, and development of immunotherapy

Cited by 85 publications

References 121 publications

Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

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

Lck-Dependent Tyrosine Phosphorylation of Diacylglycerol Kinase α Regulates Its Membrane Association in T Cells

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