中科院细胞与分子免疫学课程Chapter6

Chapter 6 Antigen Receptors and Accessory Molecules of T Lymphocytes,T cell receptor and accessory molecules:,According to function, the molecules of the T cell surface are divided into : TCR: recognition antigen Stable adhesion molecules Signaling,T Cell Receptor,Structure of the TCR,Structure of the TCR,1) V contain CDR, three CDR in chain are juxtaposed to three similar regions in the chain.2) The chain of V domain contains a fourth hypervariable region in the binding superantigens.3) C contain positively charged amino acid residues, lysine in chain or lysine and an arginine in chain., TCR,NK-T Cell,A small population of T cells express markers that are found on NK cells that are called NK-T cells.TCR recognize lipids that are bound to CD1 molecules.,T Cell Receptor,Role of the TCR in the Recognition of MHC-Associated Peptide Antigen,CDR1 are positioned over the ends of the bound peptides.CDR2 are over the helices of the MHC molecules.CDR3 are positioned over the center of the MHC-associated peptide.Only one or two amino acid residues of the MHC-bound peptide make contact with the TCR.The affinity of the TCR for peptide-MHC complexes is low.,Role of the TCR in contact with MHC-peptides complex,Role of the TCR in contact with MHC-peptides complex,T cell receptor complex,Structure and Association of CD3 and Proteins,The association were identified by Co-IP experiment.The CD3 , , and proteins are homologous to each other .Members of Ig superfamily.The transmembrane segments contain a negatively charged aspartic acid residue.The cytoplasmic domains contain one copy of ITAM.ITAM: important for signaling functions that is called immunoreceptor tyrosine-based activation motif.( tyrosine-x-x-leusine)chains has a long cytoplasmic region contain three ITAMs.,The expression of the TCR complex requires synthesis of all its components,The entire TCR complex is assembled in the ER, transport to the Golgi complex where carbohydrates are added and modified.,Functions of CD3 and Proteins,Antibodies against CD3 proteins are polyclonal activators of T cells.The cytoplasmic tail of either the CD3 or the protein is sufficient to transduce the signals necessary for T cell activation.After antigen recognition , ITAM are phosphorylated, become docking sites for adapter（衔接蛋白） proteins and tyrosine kinases（酪氨酸激酶）.,Lck,Fyn,CD45,P,MHC II,CD4,Accessory Molecules of T Cells,Several integral membrane proteins in response to antigen recognition dont belong to the members of the TCR complex. Some of these accessory molecules roles are in transducing signals that are involved in T cell activation. Some of these accessory molecules roles are in strengthening the adhesions between T cells and other cells.,Accessory（辅助） molecules in regulating activation of T cells,Two signals were needed in T cell activation The first signal: TCR and coreceptor binding to the peptides-MHC complexes.The second signal: costimulators,Accessory molecules in regulating activation of T cells,1.The first signal : Coreceptors, CD4 and CD8, operate together with the TCR complexes in recognition of MHC molecules and in T cell activation.,In signal transduction at the time of antigen recognition.Strengthen the binding of T cells to APCs.65% of mature -positive T cells in the blood and lymphoid tissues express CD4, and 35% express CD8.,Structure of CD4,CD4 is expressed as a monomer on the surface of T cells, phagocytes and some dendritic cells.CD4 has four extracelluar Ig- like domains.Its two N-terminal Ig-like domains binds to the 2 domain .,HIV receptor,Structure of CD8,Disulfide linked heterodimers（异二聚体） composed of two related chains called CD8 and CD8 .The Ig domain of CD8 binds to nonpolymorphic 3 domain of class I MHC molecules.,Functions of CD4 and CD8,CD4 binding to class II MHC,CD4+ T cell responds to extracellular antigen,CD8 binding to class I MHC,CD8+ T cell responds to intracellular antigen,CD4 and CD8 molecules are essential in the responses of T cells,CD4 and CD8 molecules are essential in the responses of T cells,The reason:,1). After T cell recognition of peptide-MHC complexes, CD4 and CD8 participate the early signal transduction events.,Lck,Fyn,CD45,P,MHC II,CD4,Lck（酪氨酸激酶）: Src family tyrosine kinase that is noncovalently but tightly associated with the cytoplasmic tails of both CD4 and CD8.When a T cell recognizes the antigen, the associated Lck will be activated and participate in initiating the T cell activation cascade.,2). CD4 and CD8 promote the T cells adhesion to APC and target cells,TCR,2. The second signal : the interaction between CD28 or CTLA-4 with B7 regulate T Cell activation,CD28: which is expressed on more than 90% of CD4+ T cells and on 50%of CD8+T cells.CD28: CD28 is a homodimer of two chains with Ig domains.B7: B7-1 and B7-2 are expressed on professional APCs.CD28 binding of B7 delivers signals to the T cells that inducethe expression of anti-apoptotic proteins stimulate production of growth factors other cytokinespromote T cell proliferation and differentiation.,Activation:,Inhibition:,CD152 : B7 is to inhibit T cell activation,CD152: CTLA-4( Cytotoxic T lymphocyte antigen-4) the structure is homologous to CD28.CD152 expression: On the surface of recently activated CD4+and CD8+ T cells.,3. Other Accessory Molecules with Signaling Functions: CD2,1) CD2 expression: is a glycoprotein present on more than 90% of mature T cells, on 50% to 70% of thymocytes, on NK cells.2) CD2: two extracellular Ig domain, a hydrophobic transmembrane region, and a long cytoplasmic tail.3) The functions of CD2 are in intercellular adhesion and as a signal transducer.Some anti-CD2 antibodies increase cytokine secretion Some anti-CD2 anitibodies block conjugate formation,E rosette: CD2 on T lymphocytes interact with CD58 on the leukocyte.,The ligand of CD2: CD58, LFA-3 ( leukocyte function-associated antigen-3),Adhesion Molecules of T Cells:,1. Play important roles in the interaction of T cells with APCs:Integrin2. In the migration of T cells to the sites of infection and inflammation:selectin,Integrins:,Heterodimeric cell surface protein .According to chain, seven integrin subfamilies were defined.The major integrin adhesion molecules on T cells are 1 and 2 integrins. 1 family called: VLA( very late activation antigens), for this integrins were first expressed on T cells 2-4 weeks after stimulation.1 family are also called CD49a-fCD29, CD49a-f: 1-6, CD29: 1,Integrins:,2 integrins called LFA, leukocyte function-associated antigen-1, were identified by monoclonal antibodies that blocked adhension-dependent lymphocyte functions such as killing of target cells by CTLs.This family is also called CD11a-cCD18, LFA-1: CD11aCD18CD11bCD18: Mac-1or CR3CD11cCD18: P150, 95 or CR43) Type 1 leukocyte adhesion deficiency(LAD-1): recurrent bacterial and fungal infections, for lack of leukocyte accumulation at sites of infection, and profound defects in adherence-dependent lymphocyte function.,Specific ligand for integrin 1 and 2.,For integrin 2:ICAM-1 or CD54: intercellular adhesion molecule-1, expressed on almost all cell surface.ICAM-2: on endothelial cellsICAM-3: on lymphocytes.For integrin 1: VCAM-1; vascular cell adhesion molecule-1, expressed on cytokine-activated endothelial cells.,IntegrinsTwo chain molecules - that bind to Ig superfamilymolecules and extracellular matrix components,INTEGRINIg FAMILY LIGANDaLb2 (LFA-1)ICAM-1,The major functions of T cell integrins are to mediate adhesion to APCs, endothelial cells and extracellular matrix proteins,The avidity of integrins and the expression of integrins will be increased by:Inflammatory CytokinesTCR recognize antigen,Integrin function:,1 retention of antigen-stimulated T cells in lymphoid organs2 retention of activated T cells at peripheral sites of infec