This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.

T cell activation.

NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

/pdf/targeting-nf-kb-pathway-for-the-therapy-of-diseases-rkkgu4xa4c.pdf

Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study.

Calcium signals in cells of the immune system participate in the regulation of cell differentiation, gene transcription and effector functions. An increase in intracellular levels of calcium ions (Ca2+) results from the engagement of immunoreceptors, such as the T-cell receptor, B-cell receptor and Fc receptors, as well as chemokine and co-stimulatory receptors. The major pathway that induces an increase in intracellular Ca2+ levels in lymphocytes is through store-operated calcium entry (SOCE) and calcium-release-activated calcium (CRAC) channels. This Review focuses on the role of Ca2+ signals in lymphocyte functions, the signalling pathways leading to Ca2+ influx, the function of the recently discovered regulators of Ca2+ influx (STIM and ORAI), and the relationship between Ca2+ signals and diseases of the immune system.

Calcium signalling in lymphocyte activation and disease.

The function of the Src-family kinases (SFKs) Lck and Fyn in T cells has been intensively studied over the past 15 years. Animal models and cell line studies both indicate a critical role for Lck and Fyn in proximal T-cell antigen receptor (TCR) signal transduction. Recruited SFKs phosphorylate TCR ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains, which then serve as docking sites for Syk-family kinases. SFKs then phosphorylate and activate the recruited Syk-family kinase. Lck and Fyn are spatially segregated in cell membranes due to differential lipid raft localization, and may undergo sequential activation. In addition to the CD4 and CD8 coreceptors, a recently described adaptor, Unc119, may link SFKs to the TCR. CD45 and Csk provide positive and negative regulatory control of SFK functions, respectively, and Csk is constitutively bound to the transmembrane adapter protein, PAG/Cbp. TCR-based signaling is required at several stages of T-cell development, including at least pre-TCR signaling, positive selection, peripheral maintenance of naive T cells, and lymphopenia-induced proliferation. SFKs are required for each of these TCR-based signals, and Lck seems to be the major contributor.

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation.

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin9s lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

/pdf/the-innate-mononuclear-phagocyte-network-depletes-b-4ry5o2ityh.pdf

The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

Essential Role of LAT in T Cell Development

We evaluated the effect of differing physical activity patterns on fibrinolysis and vasodilatory capacity using a cross-sectional design with 16 endurance-trained (ET) (mean ± SE) (28 ± 6 years), 14 resistance-trained (RT) (28 ± 7 years), and 10 untrained (UT) (26 ± 7 years) men. t-PA and PAI-1 activity and t-PA antigen were measured before and after a maximal treadmill test (VO2peak). Vasodilatory capacity was assessed using strain-gauge plethysmography on the forearm following reactive hyperemia (RH) before and after the treadmill test. The ET group had a smaller body mass index (BMI) (22.8 ± 0.5 ET, 26.4 ± 0.4 RT, 25.1 ± 0.8 UT kg m−2) (P < 0.05) and a greater VO2peak (57 ± 1 ET, 42 ± 2 RT, 45 ± 2 UT mL min−1 kg−1) (P < 0.05). Peak vasodilatory capacity (29.7 ± 2 ET, 32.0 ± 2 RT, 27.4 ± 2 UT mL min−1 100 mL of tissue) was similar between groups before and after exercise. Area under the curve for forearm blood flow was greater following acute exercise (212 vs. 122, P < 0.05), again with no differences between groups. t-PA activity and antigen increased following maximal exercise in all groups (P < 0.0001), with no group differences. PAI-1 activity decreased the least in RT after exercise (70% decrease vs. 86% ET and 82% UT; P < 0.05). The change in t-PA activity with exercise was not related to exercise-induced change in overall vasodilatory capacity. These findings demonstrate that in healthy young men different physical activity patterns do not appear to impact the exercise-induced changes in fibrinolysis or vasodilatory capacity.

Fibrinolytic markers and vasodilatory capacity following acute exercise among men of differing training status.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Helena M. Jacobs

Author Tools

Chat about Author

Papers

Essential Role of LAT in T Cell Development

Fibrinolytic markers and vasodilatory capacity following acute exercise among men of differing training status.