T-cell activation is essential in the immune response, specifically in the adaptive immune system. T cells, a type of lymphocyte, play a central role in coordinating and executing immune responses against specific pathogens.
Activation of mature peripheral T cells begins with the interaction of the T-cell receptor (TCR) with an antigenic peptide displayed in the groove of an MHC molecule. Although the TCR governs the TCR governs, the specificity of ow avidity necessitates the involvement of coreceptors and other accessory membrane molecules that strengthen the TCR-antigen-MHC interaction and transduce the activating signal.
Activation leads to the differentiation of T cells into various types of effector and memory T cells. Because the vast majority of thymocytes and peripheral T cells express the T-cell receptor rather than the T-cell receptor
Table of Contents
Steps of T cell activation
The activation process involves several steps and is tightly regulated to ensure an effective and targeted immune response.
Antigen Recognition
T-cell activation begins with the recognition of specific antigens. Antigens are fragments of proteins derived from pathogens (such as viruses or bacteria) or abnormal cells. The T cell recognizes antigen-presenting cells (APCs), primarily dendritic cells, macrophages, and B cells.
Antigen Presentation
APCs can process and present antigens on their cell surface in corporation with major histocompatibility complex (MHC) molecules. MHC class II molecules present antigens to CD4+ T cells (helper T cells), while MHC class I molecules present antigens to CD8+ T cells (cytotoxic T cells).
T Cell Receptor (TCR) Engagement
T cells express TCRs on their surface, interacting with the presented antigen-MHC complex on APCs. This interaction is particular, and the binding of the TCR to the antigen-MHC complex is a critical event in T cell activation.
Co-stimulation
In addition to TCR engagement, co-stimulatory signals are required for full T-cell activation. Co-stimulatory molecules, such as CD28 on T cells and B7 on APCs, interact to provide the necessary secondary signals. This helps prevent inappropriate activation and ensures T cells respond only to genuine threats.
Signal Transduction
The binding of the TCR to the antigen-MHC complex, along with co-stimulatory signals, initiates intracellular signaling pathways within the T cell. This activates various proteins and transcription factors, including those involved in cytokine production and cell proliferation.
Clonal Expansion
Activated T cells undergo clonal expansion, rapidly expanding to generate a large population of effector T cells. This expanded T cell population includes both effector T cells, which carry out immune functions, and memory T cells, which provide long-term immunity.
Differentiation into Effector T Cells
CD4+ T cells differentiate into various effector T cell subsets, such as Th1, Th2, Th17, or regulatory T cells (Tregs), depending on the cytokine microenvironment. CD8+ T cells differentiate into cytotoxic T cells capable of directly killing infected or abnormal cells.
Migration to Site of Infection
Activated T cells, both CD4+ and CD8+, migrate to the site of infection or inflammation through the bloodstream. Chemokines and adhesion molecules facilitate their homing to specific tissues.
Effector Functions
Effector T cells carry out their functions, including activating other immune cells, producing cytokines, or directly killing infected or abnormal cells. This phase is essential for eliminating the threat and resolving the infection.
Contraction and Memory Formation
After clearing the pathogen, most effector T cells undergo apoptosis (programmed cell death), reducing the T cell population. However, a subset of T cells transforms into memory cells, providing long-lasting immunity and faster response upon re-exposure to the same antigen.
Biological Pathways for T-cell Activation
When T cells recognize antigens and costimulators, they express proteins involved in proliferation, differentiation, and effector functions. Naive T cells that have not interacted with antigens (so-called resting cells) have a low level of protein synthesis.
Within minutes of antigen recognition, new gene transcription and protein synthesis are seen in the activated T cells. The biochemical pathways that link antigen recognition with T-cell responses consist of activating enzymes, recruiting adapter proteins, and producing active transcription factors.
Generation of Intracellular Signals
Several transmembrane signaling proteins, including the CD3 and ζ chains, are associated with the TCR. CD3 and ζ contain tyrosine-rich motifs, called immuno-receptor tyrosine-based activation motifs (ITAMs), critical for signaling. Once it is activated. Lck phosphorylates tyrosine residues contained within the lTAMs of the ζ and CD3 proteins. The phosphorylated ITAMs of the ζ chain become docking sites for a tyrosine kinase called ZAP-70 (ζ-associated protein of 70 kD), which is also phosphorylated by Lck and made enzymatically active. The active ZAP-70 then phosphorylates various adapter proteins and enzymes, which assemble near the TCR complex and mediate additional signaling events.
Signaling Pathways
Two major signaling pathways linked to ζ chain phosphorylation and ZAP-70 are the calcium-NFAT and the Ras/Rac kinase pathways.
Calcium-NFAT Pathways
NFAT (Nuclear factor of activated T cells) is a transcription factor whose activation is dependent on Ca2+ ions. The calcium-NFAT pathway is initiated by ZAP-70-mediated phosphorylation and activation of an enzyme called phospholipase C (PLC), which catalyzes the hydrolysis of plasma membrane inositol phospholipids. One byproduct of PLC-mediated phospholipid breakdown, called inositol 1,4,5- triphosphate (IP3), stimulates the release of Ca2+ ions from intracellular stores. At the same time, signals from the TCR complex lead to the influx of extracellular Ca2+ in the cell. Cytoplasmic Ca2+ binds a calmodulin protein, and the Ca2+-calmodulin complex activates a phosphatase called calcineurin. This enzyme removes phosphates from a nuclear factor of activated T cells, called an inactive cytosolic transcription factor.
Once dephosphorylated, NFAT can migrate into the nucleus, where it binds to the promoters of several genes, activating them. A drug called cyclosporin binds to and inhibits calcineurin’s activity, thus inhibiting the production of cytokines by T cells. This agent is widely used as an immunosuppressive drug to prevent graft rejection; its advent has been one of the significant factors in the success of organ transplantation in the past decade.
Ras/Rac-MAP Kinase Pathways
The Ras/Rac-MAP kinase pathways include the guanosine diphosphate (GTP) binding Ras and Rac proteins, which are biologically active when bound to GTP, several adapter proteins, and a cascade of enzymes that eventually activate one of a family of mitogen-activated protein (MAP) kinases. The pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adapter proteins at the plasma membrane, leading to the recruitment of Ras or Rac and their activation by exchange of GTP and guanosine diphosphate (GDP). Both Ras-GTP and Rac-GTP initiate different enzyme cascades that leado the activation of distinct MAP kinases. The terminal MAP kinases in these pathways, called extracellular signal-regulated kinase (ERK) and cJun amino(N)-terminal kinase WK), promote the expression of a protein called c-Fa and the phosphorylation of another protein called c-Jun. C-Fos and phosphorylated c-Jun combine to form the active transcription factor AP-1 (activating protein-1 ). which enhances the transcription of several T-cell genes.
Other Biochemical Events
Other biochemical events involved in TCR signaling include the serine-threonine kinase called protein kinase C (PKC), which activates the transcription factor nuclear factor-kb (NF-κB). PKC is activated by diacylglycerol, which, like IP3, is generated by phospholipase C-mediated hydrolysis of membrane inositol lipids. A T cell-specific PKC isoform, PKC-θ, is linked to NF-κB activation. NFκB exists in the cytoplasm of resting T cells in an inactive form, which binds to an IKB inhibitor. TCR signals generated by antigen recognition lead to phosphorylation and dissociation of the NF-κB-bound inhibitor. As a result, NF-κB is released and can move to the nucleus, activating the transcription of several genes.
The transcription factor, NFAT, AP-I, and NF-κB, stimulate transcription. After that production of cytokine receptors, cell cycle inducers, and effector molecules such as CD40L occurs. All the signals are initiated by antigen recognition because binding the TCR and coreceptors to antigen (peptide-MHC complexes) is necessary to assemble the signaling molecules and initiate their enzymatic activity.
The recognition of costimulators, such as B7 molecules, by their receptor (i.e., CD28) is essential for complete T-cell responses. The signals transduced by CD28 on binding to B7 costimulators are even less defined than TCR-triggered signals. CD28 engagement amplifies TCR signals, or CD28 initiates a distinct set of signals that complement TCR signals. These possibilities, of course, are not mutually exclusive.
References
- Abbas, A. K., & Lichtman, A. H. (2006). Basic immunology: Functions and disorders of the immune system. Elsevier Saunders.
- Kuby Immunology, 8th Edition
