BMS/PDA II-Immun 5 Cell Mediated Immunity PDF

BMS/PDA II-Immun 5 Cell Mediated Immunity Dr. Saber Hussein  Learning Objectives Activation of T lymphocytes by cell-associated microbes Phases of T cell responses Antigen recognition and costimulation Recognition of MHC-associated peptides Role of adhesi...

BMS/PDA II-Immun 5 Cell Mediated Immunity Dr. Saber Hussein  Learning Objectives Activation of T lymphocytes by cell-associated microbes Phases of T cell responses Antigen recognition and costimulation Recognition of MHC-associated peptides Role of adhesion molecules in T cell activation Role of costimulation in T cell activation Responses of T lymphocytes to antigens and costimulation Secretion of cytokines and expression of cytokine receptors Clonal selection and expansion Differentiation of naïve T cells into effector cells Development of memory T lymphocytes Biochemical pathways of T cell activation Microbial evasion of cell-mediated immune response  Effector mechanisms of cell-mediated immunity Types of cell-mediated immunity Migration of effector T lymphocytes to sites of infection Effector functions of CD4+ T lymphocytes T cell-mediated macrophage activation Elimination of microbes by activated macrophages Role of TH2 cells in cell-mediated immunity Effector functions of CD8+ cytolytic lymphocytes Resistance of pathogenic microbes to cell-mediated immunity  CD4+ TH1 Cellular Fig Fig 6-1 6-1 immunity against intracellular microbes Effector T cells of the CD4+ TH1 subset recognize the antigens of microbes ingested by phagocytes and activate the phagocytes to kill the microbes and induce inflammation Phagocyte activation and inflammation are responses to cytokines produced by the T cells  CD8+ CTLs Cell-mediated immunity against intracellular Fig 6-1 microbes CD8+ T cells produce cytokines that elicit inflammatory and M reactions CD8+ T cells recognize microbial antigens in the cytoplasm of infected cells CD8+ CTLs kill infected cells with microbes in the cytoplasm [CTLs: cytolytic T lymphocytes] Fig 6-2 The induction and effector phases of cell-mediated immunity Induction of response: CD4+ T cells & CD8+ T cells recognize peptides that are derived from protein antigens and presented by professional APCs in peripheral lymphoid organs The T lymphocytes are stimulated to proliferate and differentiate, and effector cells enter the circulation Migration of effector T cells and other leukocytes to the site of antigen: – Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues.  Migration of naive and effector T cells A. Naive T lymphocytes home to lymph nodes as a result of L-selectin binding to its ligand on high endothelial venules (HEVs), which are present only in lymph nodes Activated T lymphocytes, including effector cells, home to sites of infection in peripheral tissues, and this migration is facilitated by: – E-selectin Ligand → E-selectin – P-selectin Ligand → P-selectin – Integrins: LFA1 ➔ ICAM-1 (ligand) VLA4 ➔ VCAM-1 (Ligand) Chemokines that are produced in lymph nodes and sites of infection also participate in the recruitment of T cells to these sites (see next, Fig 6-3)  Migration of naive and effector T cells Fig 6-3 HEV E-selectin: Endothelial L-selectin: Leukocytes P-selectin: Platelets & endothelial  Migration of naive and effector T cells B. The functions of the principal T cell homing receptors and their ligands Fig 6-3 E- & P-S ligand LFA-1  Immunity to the intracellular bacterium, Listeria monocytogenes is Cell-mediated Lymphocytes or serum (a source of antibodies) was taken from a mouse that had previously been exposed to a sublethal dose of Listeria bacteria (immune mouse) and ➔Transferred to a normal (naive) mouse (see next, Fig 6-5) ➔The recipient of the "adoptive transfer" was challenged with the bacteria The numbers of bacteria were measured in the spleen of the recipient mouse to determine if the transfer had conferred immunity Manifestations of listeriosis include Gram-positive 1. Septicemia L. monocytogenes 2. Meningitis (or meningoencephalitis) 3. Encephalitis 4. Corneal ulcer 5. Pneumonia 6. Intrauterine or cervical infections in pregnant women, which may result in spontaneous abortion (2nd/3rd trimester) or stillbirth Immunity to the intracellular bacterium, Listeria monocytogenes is Cell-mediated A. Protection against bacterial challenge was induced by the transfer of immune T cells – seen by reduced recovery of live bacteria B. No protection was conferred by the transfer of serum Fig 6-5 Specificity  Cell-mediated immunity to The bacteria were killed in vitro by Listeria monocytogenes activated macrophages but No killing by T Fig 6-5C: cells ➔Protection is Elimination dependent on antigen-specific T lymphocytes Bacterial killing is the function of activated macrophages  Activation of macrophages by T cells (see Fig 6-9, next) Effector T (TH1?) lymphocytes recognize the antigens of ingested microbes on macrophages In response to this recognition, the T lymphocytes express CD40L, which engages CD40 on the macrophages, and the T cells secrete IFN-g, which binds to IFN-g receptors on the macrophages This combination of signals activates the macrophages to – Produce microbicidal substances that kill the ingested microbes – Secrete cytokines that induce inflammation (TNF, IL-1, chemokines) activate T cells (IL-12) – Express more MHC molecules and costimulators, which enhance T cell responses  Activation of macrophages by T cells The illustration shows a CD4+ T cell recognizing class II MHC-associated peptides & activating the M, but the same reaction may be elicited by a CD8+ T cell that recognizes class I MHC-displayed peptides derived from cytoplasmic microbial Ags Fig 6-7  Fig 6-8: Cytokine-mediated Macrophages that interactions between T encounter microbes lymphocytes and macrophages secrete the cytokine IL- 12 in cell-mediated immunity IL-12 stimulates naive CD4+ T cells to: – Differentiate into IFN- g-secreting TH1 cells and – Enhances IFN-g production. IFN-g activates the macrophages to kill ingested microbes  The balance between TH1 and TH2 cell activation determines the outcome of intracellular infections Naive CD4+ T lymphocytes may differentiate into – TH1 cells, which activate phagocytes to kill ingested microbes, and – TH2 cells, which inhibit macrophage activation The balance between these two subsets may influence the outcome of infections, as illustrated by Leishmania (parasite) infection in mice & leprosy (Mycobacterium leprae) in humans Both agents are intracellular → need cell-mediated immunity (see Fig 6-9, next) Fig 6-9: TH1/TH2  Mechanisms of killing of infected Fig 6-10 cells by CD8+ CTLs CTLs recognize MHC-I-associated peptides of cytoplasmic microbes in infected cells CTLs form tight adhesions conjugates Adhesion molecules, such as integrins, stabilize the binding of the CTLs to infected cells The CTLs are activated to release ("exocytose") their granule contents toward the infected cell (referred to as "targets" of CTL killing) The granule contents include: – Perforin, which forms pores in the target cell membrane, and – Granzymes, which enter the target cell through these pores (or by receptor- mediated endocytosis) and induce apoptosis.  Granzymes Granule-associated killing mechanisms  Cooperation between In a macrophage infected by an intracellular bacterium, CD4+ and CD8+ T cells some of the bacteria are in the eradication of sequestered in vesicles (phagosomes) and others may intracellular infections escape into the cytoplasm Fig 6-11 CD4+ T cells recognize antigens derived from the vesicular microbes and activate the macrophage to kill the microbes in the vesicles CD8+ T cells recognize antigens derived from the cytoplasmic bacteria and are needed to kill the infected cell, thus eliminating the reservoir of infection Evasion of cell-mediated immunity by microbes Different bacteria & viruses resist the effector mechanisms of cell-mediated immunity by different mechanisms: – Inhibition of phagosome-lysosome fusion Mycobacterium tuberculosis- cord factor – Inhibition of Ag presentation HSV peptide interference with TAP transporter Inhibition of proteasomal activity (CMV, EBV) Removal of MHC I from ER (CMV) Fig 6-12 Evasion of cell-mediated immunity by microbes Fig 6-12 Evasion of cell-mediated immunity by microbes – IL-10 production → inhibition of M activation (EBV) – Inhibition of effector cell activation by soluble cytokine receptor (IL-1R, IFN-γR by Pox virus) Fig. 6-12