Immunological synapse

Basic of Immunological synapse

1. IMMUNOLOGICAL SYNAPSE Presented by- Budha Ratna Rav

2. Meaning of Immunological synapse Immunological synapse formation Formation of mature immunological synapse Mechanism of Synapse assembly formation Molecular architecture of immunological synapse Signaling through immunological synapse Conclusion Reference Overview

3. Immunological synapse is specialized signaling area at interface between T-lymphocytes and Antigen presenting cells(APCs). Immunological synapse have three main components: 1)T-cell receptor (TCR), Adhesion molecules and co-stimulatory molecules. Term given by M Norcross . Activation of T-lymphocytes and secretes the cytokines and chemokines. Meaning of Immunological synapse: Important properties of immunological synapse: Cells remain individuals. Adhesion. Stability. Directed secretions.

4. Immunological synapse formation 1)Interaction between T-lymphocyte and APCs. This interaction is mediated by Adhesion molecule LFA-1 on T-cell and ICAM on APCs. 2)Upon conjugation of T-cell with APCs, T-cell stop their migration. 3)After conjugation T-cell get polarized.

5. Molecular Redistribution to form mature immunological synapse Initially TCR-pMHC complexes accumulate at the periphery of contact site between T-cell and pMHC lipid bilayer. Binding between LFA-1 & ICAM initially detected at the center of contact. This synapse formation is referred as pre-mature synapse. Within minutes after contact formation the molecule pattern get reversed that structure is referred as mature immunological synapse. Formation of mature immunological synapse

6. Synapse assembly formation is achieved by two mechanisms: Diffusion: In resting condition intracellular molecules are randomly laterally diffuses. Upon conjugate formation with APC-diffusion molecules are slowed or arrested in regions where new interaction with immobile ligands. Cytoskeletal driven movement: When T-cells are treated with Cytochalasin-D , shows the defects in formation of immunological synapse. Defects in cytoskeletal components such as Vau-1, Rac also shows the defects in immunological formation. Mechanism of Synapse assembly formation

7. Within 5-30 minutes after the productive engagement of TCR a mature immunological synapse is assembled. Kupfer described this assembly as Supramolecular activation cluster (SMAC). SMAC contains the three components: cSMAC, pSMAC, dSMAC. cSMAC- Enriched in the TCRs, CD2, CD4/CD8 molecules. pSMAC- Cell adhesion molecules are present such as LFA1, Cytoskeletal linker talin. dSMAC- Costimulatory molecules are present such as CD43, CD45. Molecular architecture of immunological synapse

8. Signaling through immunological synapse TCR is a multimeric protein complex is made up of six different subunits α, β, γ , δ, ε and ζ. α, β heterodimer is responsible for the Antigen recognition. CD3 chains ( γ, δ, ε) and ζ homodimer for signal transduction. TCR when engaged with pMHC-II, the cytoplasmic domains of the CD3 subunits and ζ homodimer get phosphorylated by p56-Lck and Fyn. ZAP70 is activated by PTK, phosphorylation of TCR. ZAP70 activate the LAT(Linker activation of T-cell) and phosphorylated LAT serves as docking site for multiple adaptor molecules that help in the expression of cytokine gene. Activation of LAT activates the four different intracellular transduction pathway for expression of cytokine gene.

9. Calcineurin pathway (Represent the signaling in violet color): PLC- γ bids to the phosphorylated LAT via its SH2 domain and is activated by phosphorylation of tyrosine residues by ZAP70, Itk and Fyn. Activated PLC hydrolyses phosphatidyl inositol 3- phosphate into Inositol-3-phosphate (IP3) and DAG. IP3 is released into cytoplasm and binds to own receptor on ER membrane. Upon IP3 receptor binding, Ca2+ stores in ER released into cytoplasm. This initial increase in concentration of Ca2+ opens Ca2+ release activated channels at the plasma membrane leads to the entry of Ca2+ ion into cytoplasm. Increase in the level of Ca2+, activate the protein phosphatase calcineurin which turn to dephosphorylate the transcription factor nuclear factor of T-cell (NFAT). NFAT enters in to the nucleus of T-cell and activate the transcription of cytokine genes.  

10. PKC -θ pathway:(Represents in orange color) After the hydrolysis of phosphatidyl inositol 3- phosphate, The DAG remains in the T-cell where it activates the Serine/Threonine kinase PKC -θ . PKC -θ induce the phosphorylation and consequent in ubiquitination of Ik β. Ubiquitinated Ik β is degraded by proteasomes and release the transcription factor NFkβ. NFkβ enters into the nucleus and activate the transcription of cytokine gene.  

11. Ras/ERK pathway (Green): Phosphorylated LAT serves as docking site for adopter molecule Grb2 that binds to the Ras-GDP/GTP exchange factor. After binding of Grb2 to Ras-GDP/GTP get activated. Ras activated the cascade of serine/threonine kinase that leads to the activation of MAP-kinase(Erk1/2). Erk1/2 activation leads to the expression of Fos. Fos helps in the expression of cytokine gene.  

12. Conclusion Immunological synapse has no specification in function but is simply the manifestation of signal transmission between APCs and T-cell. IS play role in the activation of T-cell by which activated T-cells shows the effect of cellular mode of immunity as well as humoral immunity.

13. Reference