Cellular Immune Response Pt 1 PDF

FDA approves CAR T cell therapy “Yescarta” 10.19.2017 To treat adults with certain types of large B-cell lymphoma who have not responded or relapsed after two rounds treatment. Patients would receive only a single treatment of Yescarta Therapy developed by Kite Pharmaceuticals. It uses technology ca...

FDA approves CAR T cell therapy “Yescarta” 10.19.2017 To treat adults with certain types of large B-cell lymphoma who have not responded or relapsed after two rounds treatment. Patients would receive only a single treatment of Yescarta Therapy developed by Kite Pharmaceuticals. It uses technology called CAR T cells – genetically engineered T cells with a chimeric antigen receptor. Price tag: $373 000. Mechanism of action Cellular Immune Response I Activation of T Lymphocytes Felix N. Toka DVM, PhD, DSc. Professor, Veterinary Virology & Immunology Department of Biomedical Sciences Objectives Revision – antigen processing and presenting pathways Understand initiation of T lymphocytes activation Regulation of T lymphocyte activation Understand functional responses of T cells Understand T cell differentiation into effector and memory cells Antigen presentation to Naïve T cells: Role of dendritic cells in initiating T-cell responses T-cell responses are initiated in the peripheral lymphoid organs, to which protein antigens are transported after being collected from their portal of entry Dendritic cells that are resident in epithelia and tissues, capture protein antigens and transport them to draining lymph nodes Several properties of dendritic cells (DCs) make them the most effective APCs for initiating primary T-cell responses DCs are strategically located at common sites of entry of microbes and in tissues that may be colonized by microbes Dendritic cells express receptors that enable them to capture microbes and respond to microbes They preferentially migrate to T-cell-rich zones of lymph nodes through which naïve T-cells circulate Mature dendritic cells express high levels of co-stimulatory molecules, which are needed to activate naïve T-cells Dendritic cells can ingest infected cells and tumor cells and present antigens from these cells to CD8+ T cells Activation of T cells Naïve T cells circulate in secondary lymphoid organs Naïve T cells acquire powerful functional capabilities only after they are activated Antigen recognition by T cells leads to activation in form of: cytokine secretion proliferation - increase in the numbers of T cells of a specific clone differentiation of the naive cells into effector and memory T cells Signals for T Lymphocyte Activation Recognition of antigen is the 1st signal for the activation of T cells CD4+ and CD8+ T cells recognize peptide-MHC complexes on APCs MHC MHCI Several other T cell surface proteins participate in the process of T cell activation REMEMBER Naïve T cells are activated by dendritic cells Dendritic cells present peptides: from endocytosed protein antigens in association with class II MHC molecules to naïve CD4+ T cells from cytosolic and nuclear proteins displayed by class I MHC molecules to naïve CD8+ T cells The 2nd signal(s) for T cell activation is called costimulation Signal 2 functions together with antigen (signal 1) to stimulate T cells Functions of costimulators in T cell activation Signal 2 - CD28:B7 works in cooperation with antigen recognition to promote the survival, proliferation, and differentiation of the specific T cells Mechanisms of T cell costimulation by CD28 CD40L:CD40 interaction enhances T cell responses by activating the APCs Role of CD40 in T cell activation Regulation of T cell activation T cell activation is influenced by a balance between engagement of activating and inhibitory receptors of the CD28 family The inhibitory receptors of the CD28 family are CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed death 1) Regulation of T cell activation cont’d CD28:B7 interaction is most important for initiating responses by activating naïve T cells ICOS:ICOS-ligand interactions are critical for helper T cell-dependent antibody responses CTLA-4:B7 interactions inhibit the initial activation of T cells in secondary lymphoid organs PD1:PD-ligand interactions inhibit the activation of effector cells in peripheral tissues REMEMBER Therapeutic Costimulatory Blockade CTLA-4-Ig is an approved therapy for rheumatoid arthritis and transplant rejection CTLA-4-Ig is in clinical trials for the treatment of psoriasis and Crohn’s disease The mechanism of therapeutic costimulatory blockade REMEMBER Therapeutic Costimulatory Blockade cont’d Inhibitors of the CD40L:CD40 pathway are also in clinical trials for transplant rejection and chronic inflammatory diseases Antibodies against CTLA-4 and PD-1 are approved or are in clinical trials for the immunotherapy of tumors Selected readings: Functional Responses of T Cell Activation 1. Increase in surface molecule expression CD69 CD25 (IL-2Rα) CD40L (CD40L, CD154) CTLA-4 (CD152) Adhesion molecules Chemokine receptors Changes in surface molecules after T cell activation Time line Changes in surface molecules after T cell activation 2. IL-2 Secretion and IL-2Rα Expression IL-2 is a growth, survival, and differentiation factor for T cells It is produced mainly by CD4+ T cells early after antigen recognition and co-stimulation It acts on the same cells that produce it or on adjacent cells Regulation of IL-2 receptor expression Functions of IL-2 stimulates the survival, proliferation, and differentiation of antigen-activated T cells increases production of IFN-γ and IL-4, by T cells is required for the survival and function of regulatory T cells Biologic actions of IL-2 Selected readings: Therapeutic use of IL-2 3. Clonal Expansion of T Cells Proliferation results in increase in number of the antigen-specific clones - clonal expansion 1 2 2 2 Definition of clonal expansion: Production of daughter cells all arising originally from a single cell. In a clonal expansion of lymphocytes, all progeny share the same antigen specificity 2 2 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 http://users.ox.ac.uk/~path0116/tig/clons.gif Clonal Expansion of T Cells cont’d Before antigen exposure, the frequency of naive T cells specific for any antigen is 1 in 105 to 106 T cells After antigen exposure, the frequency of CD8+ T cells specific for that antigen increases to 1 in 3 CD8+ T cells and 1 in 100 CD4+ T cells Clonal expansion of T cells Differentiation of Activated T Cells into Effector Cells Effector CD4+ cells express surface molecules and secrete cytokines that activate other cells (B lymphocytes, macrophages, and dendritic cells) Effector CD8+ cells are cytotoxic cells and kill infected cells Development of Memory T Cells T cell-mediated immune responses to an antigen usually result in the generation of memory T cells specific for that antigen, which may persist for years, even a lifetime “…the success of vaccination is attributed in large part to the ability to generate memory cells on initial antigen exposure. Edward Jenner’s classic experiment of successful vaccination of a child against smallpox is a demonstration of a memory response”. Abbas. et al. Cellular and Molecular Immunology, 6th Edition Development of Memory T Cells cont’d Memory cells may develop from: effector cells along a linear pathway effector populations in divergent differentiation Development of memory T cells Properties of Memory T Cells increased expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) responsible for their prolonged survival (long-lived cells) respond more rapidly to antigen stimulation than naive cells specific for the same antigen the number of memory T cells specific for any antigen is greater than the number of naive cells specific for the same antigen Properties of Memory T Cells cont’d are able to migrate to peripheral tissues and respond to antigens at those sites undergo slow proliferation in the absence of antigen - self-renewal for prolonged life span of the memory pool maintenance of memory cells is dependent on cytokines (IL-7) but does not require antigen recognition Decline of T Cell Responses Elimination of antigen leads to contraction of the T cell response Decline is responsible for maintaining homeostasis in the immune system Decline is due to: cessation of co-stimulation cessation of growth factor production (IL-2) activation of sensors of cellular stress (such as the BH3-only protein Bim), which triggers apoptosis of T cells