To understand the interaction between T-cells and antigen presenting cells, it is important to understand what all receptors are present on these cells and how they interact. There is a series of intracellular signalling cascade that is activated when a receptor is activated, which ultimately leads to the synthesis and secretion of biochemical mediators like cytokines etc. The interface between lymphocytes and targets is termed â€˜immunological synapseâ€™ (IS).
Diagram showing Interactions between T-cells and Antigen Presenting Cells
T cell receptor (TCR):
One of the first steps in the generation of the immune response is the recognition by T lymphocytes of peptide fragments (antigens) derived from foreign pathogens that are presented on the surface of antigen presenting cells (APC). This event is mediated by the T cell receptor (TCR), which transduces these extracellular signals by initiating a wide array of intracellular signalling pathways. The T cell receptor (TCR) is a complex of integral membrane proteins that participates in the activation of T cells in response to the presentation of antigen by antigen presenting cells. MHC (Major Histocompatibility Complex) molecules on Antigen Presenting Cells that present antigen peptides to TCR complexes trigger TCR and induce a series of intracellular signalling cascades. Engagement of the TCR with antigen presenting cells initiates positive (signal-enhancing) and negative (signal-attenuating) cascades that ultimately result in cellular proliferation, differentiation, Cytokine production, and/or activation-induced cell death.
TCR is composed of six different chains that form the TCR heterodimer responsible for ligand recognition. CD3 molecules (CD3-g, CD3-d, CD3-e, and CD3- z), which are assembled together with the TCR heterodimer, possess a characteristic sequence motif for tyrosine phosphorylation, known as ITAMs (Immunoreceptor Tyrosine-based Activation Motifs). One of the first step following TCR activation is the activation of Src family tyrosine kinases (p56lck) that, in turn, phosphorylate phospholipase Cg1 (PLC g1). Activation of PLC g1 leads to hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2), generating diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C (PKC) that, in turn, phorphorylates Ras, a GTPase that activates Raf leading to recruitment of the MAP kinase cascade. IP3 releases calcium from its intracellular stores in the endoplasmic reticulum (ER).
Intracellular T-cell receptor signalling mechanism
The Ca2+ binds to calmodulin that, in turn, activates calcineurin, a Ca2+/calmodulin dependent protein phosphatase. NFAT, a transcriptional regulator of interleukin-2 (IL-2) gene expression, is a direct target of calcineurin. Calcineurin dephosphorylates the cytosolic component of NFAT, NFATc, which migrates to the nucleus and induces transcription of the IL-2 gene. Adhesion molecules like LFA-I interact with ICAM-I on APCâ€™s and aid in formation of immunological synapsis.
To mount an immunological response, the T cell needs to receive a second signal from an antigen-presenting cell in the form of a co-stimulatory molecule. Co-stimulatory molecules act through different T cell receptors, such as the CD28 and TNFR (tumour necrosis factor receptor) families, producing a second signal that induces T-cell activation and proliferation. The CD28 and TNFR co-stimulatory receptors possibly exert their effect through promoting more efficient signalling by concentrating the kinases and substrates that are required to initiate a signal whose affinity has been shown to increase upon stimulation.
Antigen presenting cell:
The antigen-presenting cells (APC) have antigenic peptide with a major histocompatibility complex (MHC) molecule located at their surface. Cytotoxic T lymphocytes (CTL) expressing the CD8 coreceptor recognize a peptide bound to MHC class I molecules whereas helper T cells (Th) expressing the CD4 coreceptor do so with a peptide associated to MHC class II molecules. Co-stimulatory molecules such as B7â€“1 (CD80) and B7â€“2 (CD86) are also present on APCâ€™s that inteact with CD-28 on T-cells. Adhesion molecules such as ICAM-1 present on APCâ€™s are involved in formation of strong immunological synapsisto facilitate a proper activation of T-cells.
Interactions between CD4 and MHC II-expressing antigen presenting cells
|CD-4 T-cell||Antigen Presenting Cell ...|
|CD4 (Lck)||MHC II (co-activation with TCR)|
|TCR/CD3||MHC II/peptide (activation of T cell)|
|CD28||B7-1/B7-2 (co-activation with TCR)|
Interactions between CD8 and MHC I-expressing antigen presenting cells
|CD-8 T- cell||Antigen Presenting Cell|
|CD8 (Lck)||MHC I (co-activation with TCR)|
|TCR/CD3||MHC I/peptide (activation of T cell through PIP2/DAG, IP3 pathway)|
|CD28||B7-1/B7-2 (co-activation with TCR)|
Steps in activation of T-cells:
- Antigen which is phagocytosed by Macrophage is Cleaved into polypeptides which is then transported to surface for presentation to T- cells (only foreign particles consisting of proteins are activated and process , no other molecules like fatty acids etc are presented).
- APC complex consists of both Antigen and MHC complex. If MHC class-II is associated with presenting cells, CD 4 or helper-T cells are activated and if MHC class-I associated with presenting cells, CD 8 or cytotoxic-T cells are activated. MHC complex is encoded by group of genes so different polypeptides are presented on the surface of MHC which is responsible for its diversity of Antigen presentation. MHC presents only proteins which may be derived from foreign or self proteins. It depends upon the selection of T-cells in thymus.
- Macrophage that is attached to antigen produces interleukin-1 which activates CD 4 cells.
- CD 4 interacts with MHC-2 on APC surface. This union is stabilized by other proteins LFA-1 on T-cells and ICAM 1 on APC.
- Co-stimulatory signal is formed by B7 protein on APC & CD-28 on CD-4 cells, if this signal is formed IL-2 is secreted by helper-T cells and it is this step that is useful in formation of all the functions i.e. regulator, effector, and memory functions. This is the most crucial step in T-cell activation i.e. production of IL-2. If Co-stimulatory signal is not accomplished anergy takes place.
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