The Immune Synapse PDF

The Immune Synapse Carlos A. Barrero M.D. Assistant Professor School of Pharmacy-Temple University October 3, 2024  Cell Surface Receptor  Cells have specific surface receptors that can be triggered by external ligands Immune Receptor Family  Cell surface receptors...

The Immune Synapse Carlos A. Barrero M.D. Assistant Professor School of Pharmacy-Temple University October 3, 2024  Cell Surface Receptor  Cells have specific surface receptors that can be triggered by external ligands Immune Receptor Family  Cell surface receptors serve several major functions:  The induction of intracellular signaling leading to cell activation  Adhesion of one cell to another or to the extracellular matrix  Internalization of extracellular molecules and cells  Signals are initiated by these receptors, typically involves an initial cytosolic phase when the cytoplasmic portion of the receptor or of proteins that interact with the receptor may be enzymatically modified  Leading to an activation or nuclear translocation of transcription factors that are silent in resting cells, followed by a nuclear phase when the transcription factors orchestrate changes in gene expression. 2  Cell Surface Receptor and Signal Transduction  Signal transduction also known as intracellular signaling pathways  Receptors that initiate these responses are present on the plasma membrane, where their extracellular domains recognize soluble secreted ligands or structures that are attached to the plasma membrane of a neighboring cell or to the extracellular matrix  Nuclear receptors are found intracellularly where they are activated by lipid soluble ligands that can cross the plasma membrane.  Initiation of signaling from a cell surface receptor may require ligand-induced clustering of receptor proteins, called cross-linking, or may involve a conformational alteration of the receptor induced by its association with ligand. 3 Addition/Removal of Phosphate  A common early event in signal transduction is the enzymatic addition of a phosphate residue on a tyrosine, serine, or threonine side chain in the cytosolic portion of a receptor or in an adaptor protein.  Protein kinases are enzymes that add phosphate groups onto amino acid side chains.  e.g. Protein tyrosine kinase phosphorylates specific tyrosine residues. 4  Categories of Cellular Receptors  Non-receptor tyrosine kinases: The cytoplasmic tails of the ligand-binding polypeptides of these receptors have no intrinsic catalytic activity, but a separate intracellular tyrosine kinase, known as a non-receptor tyrosine kinase, participates in receptor activation by phosphorylating specific motifs on the receptor or on other proteins associated with the receptor  Receptor tyrosine kinases (RTKs): are integral membrane proteins that activate an intrinsic tyrosine kinase domain (or domains) located in the cytoplasmic tails of the receptors when they are cross-linked by multivalent extracellular ligands.  Nuclear receptors: are typically located in or migrate into the nucleus, where they function as transcription factors. Nuclear hormone receptors, such as the vitamin D receptor and the glucocorticoid receptor, can influence events that range from development of the immune system to modulation of cytokine gene expression.  G protein–coupled receptors (GPCRs): are receptors that function by activating associated GTP-binding proteins (G proteins). A conformational change induced by the binding of ligand to this type of receptor permits the activation of an associated heterotrimeric G protein by the exchange of bound GDP with GTP. Examples of this category of receptors that are relevant to immunity and inflammation include receptors for leukotrienes, prostaglandins, histamine, complement fragments C3a and C5a, and all chemokines.  Receptor proteins of the Notch family: are involved in development in a wide range of species. The association of specific ligands with receptors of this family leads to proteolytic cleavage of the receptor and the nuclear translocation of the cleaved cytoplasmic domain (intracellular Notch), which functions as a component of a transcription complex. Notch proteins contribute to cell fate determination during lymphocyte development and may also influence the activation of mature lymphocytes. 5 Categories of Cellular Receptors 6 Categories of Cellular Receptors  Non-receptor tyrosine kinase: The cytoplasmic tails of the ligand-binding polypeptide of these receptors have no intrinsic catalytic activity, but a separate intracellular tyrosine kinase, known as non-receptor tyrosine kinase, participates in receptor activation by phosphorylating specific motifs on the receptors or on other proteins associated with the receptors  Receptor tyrosine kinase (RTKs): They activate an intrinsic tyrosine kinase domain(s) located in the cytoplasmic tails of the receptors when they are cross- lined by multivalent extracellular ligands.  Nuclear receptors: They are located in the nucleus when they function as transcription factors. Binding of a lipid soluble ligand to its nuclear receptor results in the ability of the latter either to induce transcription or to repress gene expression. e.g. steroids. 7  Immune Receptor Family  Immune receptors that activate immune cells have separate polypeptide chains for recognition and associated polypeptide chains that contain cytosolic Immunoreceptor tyrosine-based activation motifs (ITAMs).  B cell receptor (BCR), the T cell receptor (TCR), and the high-affinity receptor for IgE (FcεRI) have ITAMs motifs.  Inhibitory receptors in the immune system typically have ITIM motifs on the cytosolic portion of the same chain that uses its extracellular domain for ligand recognition.  FcγRIIB is an inhibitory receptor found on B cells and myeloid cells. PD-1, an inhibitory receptor found on T cells, also has an immunotyrosine based “switch” motif in its cytoplasmic tail 8 T Cell Receptor for Antigen  The antigen receptor of MHC-restricted CD4+ helper T cells and CD8+ cytotoxic T lymphocytes (CTLs) is a heterodimer consisting of two transmembrane polypeptide chains, designated TCR α and β, covalently linked to each other by a disulfide bridge between extracellular cysteine residues  The antigen-binding portion of the TCR is formed by the Vβ and Vα domains.  The hypervariable segment loops that form the peptide- MHC binding site are at the top 9 Binding of TCR to an MHC molecule  The V regions of the TCR α and β chains contain short stretches of amino acids where the variability between different TCRs is concentrated, and these form the hyper- variable or complementarity -determining regions (CDRs)  Three CDRs in the α chain and three similar regions in the β chain together form the part of the TCR that specifically recognizes peptide-MHC complexes. 10 Components of the TCR Complex 11 TCR Component  CD4 and CD8 are T cell coreceptors that bind to nonpolymorphic regions of MHC molecules and facilitate signaling by the TCR complex during T cell activation.  Mature αβ T cells express either CD4 or CD8 but not both. CD8 and CD4 interact with class I and class II MHC molecules, respectively, and are responsible for the class I or class II MHC restriction of these classes of T cells 12 Role of the CD4 and CD8 Coreceptors in T Cell Activation  CD4 has four extracellular Ig-like domains, a hydrophobic transmembrane region, and a highly basic cytoplasmic tail 38 amino acids long.  The two N-terminal Ig-like domains of the CD4 protein bind to the nonpolymorphic α2 and β2 domains of the class II MHC molecule.  Most CD8 molecules exist as disulfide-linked heterodimers composed of two related chains called CD8α and CD8β.  Both the CD8 α chain and the β chain have a single extracellular Ig domain, a hydrophobic transmembrane region, and a highly basic cytoplasmic tail that is about 25 amino acids long. 13 Role of the CD4 and CD8 Coreceptors in T Cell Activation 14 The Immune Synapse 15 The Immune Synapse T Cell  The synapse forms a stable contact between an antigen-specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell, including the TCR complex, coreceptors, costimulatory receptors, and adaptors.  The immune synapse provides a unique interface for TCR triggering, thus facilitating prolonged and effective T cell signaling.  The synapse ensures the specific delivery of secretory granule contents and cytokines from a T cell to APCs or to targets that are in contact with the T cell.  The synapse, may also be an important site for the turnover of signaling molecules. This degradation of signaling proteins contributes to APC the termination of T cell activation. 16 The Immune Synapse in a T cell–APC conjugate 17 Signal Transduction  Phosphorylation of proteins and lipids plays a central role in the transduction of signals from the TCR complex and coreceptors.  Even before TCR activation, there is some basal tyrosine phosphorylation of ITAM tyrosines and some recruitment of ZAP-70, to these phosphorylated ITAMs.  Within seconds of TCR ligation, Lck phosphorylates the ITAMs of the CD3 and ζ chains. 18 Calcium- and Protein Kinase C-Mediated Signaling Pathways in T Lymphocytes 19  Activation of Transcription Factors That Regulate T Cell Gene Expression  Different transcription factors are activated by different cytoplasmic signal transduction pathways, and the requirement for multiple transcription factors accounts for the need to activate many signaling pathways after antigen recognition; including those encoding cytokine receptors and effector molecules.  Three transcription factors that are activated in T cells by antigen recognition and appear to be critical for most T cell responses are nuclear factor of activated T cells (NFAT), AP-1, and NF- κB. 20