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A T-cell precursors migrate from the bone marrow to thymus Shaping the T-cell repertoire. Positive and negative selection Thymus Few TCR reacts with the MHC (about 2%) most T-cells die of neglect. ( no survival signals) α-chain rearrangement can continue until the assembly of a functional αβ receptor has been assembled. Selection of developing T-cells in the thymus Bare lymphocyte syndrome MHCI vagy MHCII deficiency Lack of CD8+ or CD4+ cells Role of co-receptors in the development of single + T-cells DC Macrophage in medulla of Thymus. Special transcription factor expressed… AIRE. Tissue spec. Antigens expressed AIRE mutaton: Autoimmune polyendocrinopathy -candidiasis-ectodermal dystrophy Multiple stages of T-cell development in the thymus Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells. Changes in the function of dendritic cells following Activation, migration to the regional lymph node, maturation Uptake of antigen, maturation Differentiation/maturation Antigen prezentation Red: lizozyme green: MHCII A naive cells meet dendritikuc cells in the secondary lymphoid organs (review) Phases of T cell response The site of interaction between T cell and APC is called The imunological synapse Clustering of the T-cell receptor and a co-receptor initiates signaling within the T cell. (review) TCR signaling T CELL ACTIVATION CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION 1. The TCR is not able to interact directly with soluble or cell-bound antigen 2. T-cell activation can be induced by antigen in the presence of acessory cells, only 3. T-cells recognize virus-infected cells ACCESSORY CELL ANTIGEN BINDING NO INTERACTION V T-CELL ACTIVATION C Antigen receptor B-CELL a/b T-CELL T CELL RECEPTOR MEDIATED SIGNALING Multisubunit Immune Recognition Receptors APC MIRR MHC Antigen Antigen TCR BCR αβ s V s s sV s C s s sC ss P P D/E X7 D/E X2 YXXL/I X7 YXXL/I ITAM Immunoreceptor Tyrosine-based Activation Motif ACTIVATION CD3 CD3 εδ s s s s εγ s s s s ζζ s s (review) Phases of T cell response (review) BCR signaling (review) TCR signaling Intracellular (cytoplasmatic) Ca2+ concentration increase The intracytoplasmatic Ca2+ increase can be monitored by fluorescent indicator dye. The intensity or the specificity of fluorescence increase paralelly with the Ca2+ concentration. Kinetic measurements connected to signaling (1.) Homogenous population – single cell property measured one after the other - timing Detected in Detected in single cell homogenous population – measured cell by cell Indicator – detection of intracellular Ca2+ signal fluorescent Ca2+ indicators Fluo-3 or Indo-1 Kinetic measurements connected to signaling (2.) Fluo-3 AM – excitable by blue light Indo-1 AM – excitable by UV light These indicator dyes connected with apolar groups (e.g. acetoxy-methylester: AM) – go across the cell membrane. In the cell, estherases cleveage these groups - the fluorochrome became polar – catched in the cell for example – ic Ca2+ signal in a single cell antigen presentation by B cell to T cell (click) THE IMMUNOLOGICAL SYNAPSE APC T APC T CELL THE INTERACTION OF T CELLS AND ANTIGEN PRESENTING CELLS interaction recognition 1 2 3 4 5 6 stabilization 7 8 separation Negulescu P.A. et. al. Immunity 4: 421-430, 1996 T-cells need two signals!!!! The role of co-stimulation Antigen presentation - T cells are co-stimulated Signal 1 antigen & antigen receptor T APC ACTIVATION Signal 2 B7 family members (CD80 & CD86) CD28 Costimulatory molecules are expressed by professional APC including dendritic cells, monocytes, macrophages, and B cells, but not by cells that have no immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc. ROLE OF CO-STIMULATION IN THE ACTIVATION OF HELPER T CELLS Th Th Th CD40L CD28 CD40 B7 B7 APC APC APC NORMAL TISSUE CELLS DO NOT EXPRESS CD40 OR B7 CO-STIMULATORY MOLECULES Mechanism of co-stimulation in T cells Antigen 1 IL-2 IL-2 IL-2Ra IL-2Ra Resting T cells Express a low affinity IL-2 receptorb and chains and produce no IL-2 Signal 1 NFAT binds to the promoter of of the a chain gene of the IL-2 receptor. The a chain converts the IL-2R to a high affinity form Mechanism of co-stimulation in T cells Costimulation Antigen Signal 2 1 2 Activates AP-1 and NFk-B to increase IL2 gene transcription by 3 fold Stabilises and thus increases the half-life of IL-2 mRNA by 20-30 fold IL-2 IL-2Ra IL-2 production increased by 100 fold overall Immunosuppressive drugs illustrate the importance of IL-2 in immune responses Cyclosporin & FK506 inhibit IL-2 by disrupting TcR signalling Rapamycin inhibits IL-2R signalling INITIATION OF T CELL PROLIFERATION IL-2R IL-2 recognition IL-2Rα costimulation IL-1R IL-1 IL-2R G0 IL-2R low affinity G1 IL-2 M G2 IL-2R high affinity S transferrin IL-2 insulin PROLIFERATION AUTOCRINE GROTH FACTOR CO-STIMULATION IS ESSENTIAL FOR PRIMING OF NAIVE T LYMPHOCYTES The antigen-specific and the co-stimulatory signals have to be induced in concert to induce T lymphocyte activation The antigen-specific and co-stimulatory signals can be delivered simultaneously by professional antigen presenting cells, only The antigen-specific and the co-stimulatory singnals has to be delivered by the same professional antigen presenting cell T CELLS REQUIRE TWO SIGNALS TO GET ACTIVATED Activated APC Resting APC B7 CD28 APC not presenting antigen B7 CD4 2 1 T-cell activation CD4 CD28 1 T-cell anergy CD4 CD28 2 No effect ANTIGEN SPECIFIC ACTIVATION, ANERGY OR NEGLECTION Anergy Antigen Naïve T cell 1 Signal 1 only IL-2 IL-2Ra Epithelial cell Self peptide epitopes presented by a non-classical APC e.g. an epithelial cell The T cell is unable to produce IL-2 and therefore is unable to proliferate or be clonally selected. Unlike immunosupressive drugs that inhibit ALL specificities of T cell, Signal 1 in the absence of signal 2 causes T cell unresponsiveness to a specific antigen Dendritic cells are sensors, gatekeepers and messengers Activation induces a phenotype essential for the initiation of the adaptive immune response ACTIVATION AND MIGRATION OF DENDRITIC CELLS TISSUE LYMPH NODE LYMPH Activated DC TISSUE Effector and memory T cells Inflammation Pathogen Naive T cells ANTIGEN Tissue DC INTERACTION OG DC AND T CELL T CELL ACTIVATION BLOOD DENDRITIC CELL T LYMPHOCITE INTERACTION IN THE LYMPHOID ORGANS Activated dendritic cells in the lymphatic tissues act as antigen presenting cells Tight contact with specific T cells DENDRITIC CELL-T CELL INTERACTIONS IN THE T-CELL AREAS OF LYMPH NODES NUCLEUS T CELL T CELL CYTOPLASM Cell-surface molecules of the immunoglobulin superfamily initiate lymphocyte adhesion to professional antigen-presenting cells B. Transient interactions are stabilized by Ag-binding A. A Initial contact Rapid DC Migration in the Subcapsular Space Bone-marrow derived DCs (green)or (50 µM Cell Tracker Blue, blue) were injected into the footpad of a C57BL/6 mouse, followed 18 hours later by intravenous injection of freshly isolated T cells ( red) Capture of an Ag-Specific T Cell by an Ag-Bearing DC Bone-marrow derived DCs (yellow) were pulsed with 1 µM Ova 4 peptide and 10 µM Ova for 1 hour at 37oC, then injected into the footpad of a C57BL/6 recipient. This was followed 6 hours later by i.v. co-injection of CD8+ T cells (green) and CD4+ T cells (red). Huang et al Immunity 2004 The stages of activation of CD4 T cells. Different cytokine environments drive the differentiation of CD4 T cells that make different cytokines and have different functions. Responses to Mycobacterium leprae are sharply differentiated in tuberculoid and lepromatous leprosy. Granulomas develop when intracellular pathogens resist elimination Long term persistance of infectious agent in a separated envitonment The three types of effector T cell produce distinct sets of effector molecules. TH1 CD4 cells activate macrophages to become highly microbicidal. TH2 cells stimulate the proliferation and differentiation of naive B cells.