Lecture 10: Lymphocyte Receptor Signaling (10/08/2024) PDF

Lecture 10 Lymphocyte Receptor Signaling 10/08/2024 Learning Objectives Co-stimulatory and Antigen receptor inhibitory receptors General principles of signaling and lymphocyte...

Lecture 10 Lymphocyte Receptor Signaling 10/08/2024 Learning Objectives Co-stimulatory and Antigen receptor inhibitory receptors General principles of signaling and lymphocyte modulate antigen signal transduction activation receptor signaling in lymphocytes Paradigm of Adaptive Immunity A primary response to an antigen causes clonal expansion of antigen- reactive T or B cells and produces a large number of effector lymphocytes that cause clearance of the pathogen. Proliferation and differentiation - directed by antigen receptors, costimulatory molecules, adhesion molecules, cytokines, and chemokines coupled to signal transduction pathways – control transcriptional and metabolic programs – determine lymphocyte function Ligand-receptor binding alters cell General principles function of signal transduction Signal transduction – the process of converting a signal from one form to another Receptor – a molecule that receives signal from its ligand, the molecule it binds Antigen is the ligand for BCR Peptide + MHC is the ligand for TCR Membrane receptors all have extracellular domains – specifically bind ligands transmembrane domains – span the plasma membrane cytoplasmic domains – participate in signal transduction How are T cells activated? B7 is a cell-surface protein on an APC. Two related B7 molecules: B7.1 (CD80) and B7.2 (CD86) T-cell activation requires binding of the T-cell receptor Expressed ONLY when an and CD28 at an infection is present immunological synapse Signal 1 Signal 2 – Costimulatory signal Naïve T cells express CD28 as a receptor for B7 molecules Image credit: Immunology by S. Juris. Oxford Press  Signal transduction in T-cell activation Immunological synapse TCR and MHC:peptide complex Co-stimulatory molecules Co-receptor and MHC:peptide complex Cell-adhesion molecules Relays the signal that a synapse has formed Image credit: Immunology by S. Juris. Oxford Press Signal transduction at the TCR complex ITAMs (immunoreceptor tyrosine-based activation motifs): cytoplasmic aa sequences containing tyrosine that are targets of phosphorylation and subsequent activation of signaling events Docking sites for other proteins Mediate the interaction with cytoplasmic protein-tyrosine kinases Lck ZAP-70 Key event - induces 3 signal transduction pathways Kinases - enzymes that catalyze the transfer of Image credit: Immunology by S. Juris. Oxford Press phosphate group from a donor to an acceptor Signaling events that induce T-cell activation PLC is a lipase PIP2: phosphatidylinositol biphosphate – a lipid IP3: inositol triphosphate DAG: diacylglycerol Step 1: phosphorylation & activation of PLC Step 2: cleavage of PIP2 into IP3 and DAG Image credit: Immunology by S. Juris. Oxford Press Signaling events that induce T-cell activation Step 3a: IP3 signals the opening of calcium stores Step 4a: Ca2+: secondary messenger – diffuse through cell to activate variety target proteins Step 5a: Calcineurin dephosphorylates NFAT (Nuclear Factor of Activated T cells) Step 6a: NFAT activates genes involved in T-cell expansion and differentiation FIRST signal transduction pathway IL-2: one of the most important gene for T-cell activation Phosphatase - enzymes that remove a phosphate group from proteins Image credit: Immunology by S. Juris. Oxford Press Signaling events that induce T-cell activation Step 3c: DAG associates with small GTPase, RAS Step 4c: RAS triggers MAP kinase Step 3b: DAG activates protein kinase C (Mitogen-Activated Protein kinase) (PKC) cascade to activate Fos Step 5c: Fos interacts with another protein, Jun, to form AP-1, a Step 4b: PKC- activates transcriptional transcriptional factor factor NF-B through the destruction of the associated IB protein Step 6c: Jun is activated through co- stimulatory signal provided by CD28 SECOND signal transduction pathway THIRD signal transduction pathway Image credit: Immunology by S. Juris. Oxford Press Multiple signaling pathways converge on the IL2 promoter Fig. 7.32 IL-2: one of the most important gene for T-cell proliferation and differentiation into effector T cells  Recall Classes of Cytokines Lecture 3? Cytokine Secreting Cells Function Inflammatory Cytokines TNF-alpha Macrophages Inflammation IL-1 Macrophages, DCs Inflammation Signaling Cytokines IL-2 T cells T-cell activation IL-4 DCs B-cell activation IL-10 Monocytes Anti-inflammatory IL-12 DCs Th1 helper T-cell activation IL-17 T cells Neutrophil activation IFN- T cells, Macrophages, NK cells Macrophage activation IFN-/IFN- Macrophages, virally-infected cells NK activation, prevention of viral replication TGF- Regulatory T cells Peripheral tolerance Chemokines CXCL8 (IL8) Monocytes, macrophages Mobilizes and activates neutrophils How are B cells activated? Responsible for signal transduction during B-cell activation (similar to TCR CD3) Image credit: Immunology by S. Juris. Oxford Press Clustering of BCR complexes drives activation Many antigens to which the receptor binds promote clustering of the receptor on the B cell surface Src family kinases: Blk, Fyn, or Lyn Image credit: Immunology by S. Juris. Oxford Press B-cell coreceptor binding B-cell coreceptor Image credit: Immunology by S. Juris. Oxford Press CR2 is responsible for the binding required for the costimulatory signal Binds to iC3b and C3d, breakdown products of C3b fixed on pathogen surface by Factor I CD19 has the cytoplasmic domain for signaling events CD81 stabilizes the coreceptor complex  Signaling at the Ig receptor complex Syk is a key kinase within B cells induces 3 signal transduction pathways – NFAT, NF-kB, and AP-1 GEFs: guanine-exchange factors Catalyze the exchange of guanine nucleotides on guanine nucleotides binding proteins Ras and Rac Image credit: Immunology by S. Juris. Oxford Press Inhibitory receptors on lymphocytes down-regulate immune responses by interfering with co-stimulatory signaling pathways PD-1 (programmed death-1) Activated T cells express CTLA4, BTLA BTLA (B and T an inhibitory receptor, instead of lymphocyte attenuator) CD28 – 20x stronger adhesion – internal check mechanism Fig. 7.34 Checkpoint questions for Lecture 10 1. What costimulatory interaction is required between T cells and APCs? 2. What is the importance of activating protein-tyrosine kinases at the initiation of the formation of an immunological synapse between T cells and APCs? 3. Clonal expansion of T cells requires the activation of transcription factors to promote gene activation. What three transcription factors are activated during T-cell activation? 4. Is binding of a single cell-surface Ig to an antigen sufficient for B-cell activation? Why or why not? 5. How is B-cell activation through BCR complex similar to T-cell activation through the TCR complex? 6. How is the transcriptional activation in B cells during their activation similar to that within T cells?