Effector Mechanisms of Cell-Mediated Immunity

Transcription

1 Effector Mechanisms of Cell-Mediated Immunity Dr. Julia Rempel Section of Hepatology D JBRC

2 Topics: I. Types of Cell-Mediated Immunity II. Migration of Effector T Lymphocytes to Sites of Infection III. Effector Functions of CD4+ Helper T Cells IV. Effector Functions of CD8+ Cytoxic T Cells V. Resistance of Pathogenic Microbes to Cell-Mediated Immunity

3 I. Types of Cell-Mediated Immunity (CMI) Describes any adaptive response in which antigen specific T cells have the main role. The effect can not be transferred by serum. Cell mediated immunity to intracellular Listeria

4 II. Migration of Effector T Lymphocytes to Sites of Infection Immune protection: fighting off the bad guys the way it is suppose to work Host Sick Monkey Liver

5 The Host Defense Local response 1. Innate immunity Activated by: - pathogen-associated molecular patterns recognized by TLR, PRR - viral replication Function: - reduce pathogen load - direct the adaptive response. (Innate activation, Chp 2)

6 Local response 1. Innate immunity 2. Dendritic cells Immature DC Long lived, Slow turn over Surveillance -receptors (eg. TLR, PRR) Ag acquisition -phagocytosis

7 Local response 1. Innate immunity 2. Dendritic cells Messenger DC afferent lymphatics Lymph Nodes At Lymph Nodes DC differentiate into mature DC - enhance co-stimulatory molecules - lose phagocytotic ability 3. T cell and B cell Adaptive response Antigen presentation to naïve T cells (Chp 5).

8 The induction and effector phases of cell-mediated immunity (Chp 5). Lymph Nodes T cell Adaptive Response T cell activation - receives antigen information T cell maturation - armed effector cell not require co-stimulation - can act directly against infected cells T cell expansion

9 Overview of migration. Similar to migration of other leukocytes (Chp 2).

10 Migration of naïve T Lymphocytes LN to blood: Decrease L Selection CCR7 Increase receptor for sphingosine 1-phosphate L-selectin/L-selectin ligand adhesion of naïve T cells to high endothelial venule in lymph node LFA-1/ICAM-1 stable stop on HEV CCL19/CCR7 chemokine/chemokine receptor - activation of intergrins and chemotaxis

11 Migration of activated T Lymphocytes Blood to Tissue: Activated cells Endotheliun (TNFα) E- and P- selectin ligand/e- and P- selectin - weak adhesion at infection site sialylated carbohydrates and glycoprotein CD162 LFA-1 or VLA-1/ICAM-1 or VCAM-1 - stable stop CXCL10/CXCR3 - activation of integrins and chemotaxis

12 Migration and retention of effector T cells at sites of infection At infection site macrophage and endothelial cell release chemokines Migration: Antigen independent Retention: Antigen dependent

13 Innate response Clean up the mess Rebuild Return to homeostasis Lymph Nodes T cell Adaptive response Store info for future conflict Shut down (die off) avoid becoming the enemy

14 Healthy Monkey

15 III. Effector Functions of CD4 + Helper T Lymphocytes A. Cell-mediated Macrophage Activation against Intracellular Microbes 1. Effector CD4 T cells (TH1) activate the macrophages

16 2. Activation of naïve CD4 T cells Abbas & Lichtman, 2008

17 B. Role of Th1/Th2 Cells in Cell-Mediated Immunity The balance between TH1 and TH2 cell activation determines outcome of intracellular infections

18 C. Regulatory T cells: (Chapter 9 - Immunological Tolerance and Autoimmunity) Disease Treg absence Treg presence Autoimmune disease Autoimmunity Homeostasis HCV infection Immune outcome Infection clearance Homeostasis Chronic infection Pathology

19 D. CD8 T cell activation and survival CD4 cell help required for CD8 cell activation CD8 cells are harder to activate naïve CD4 cells - Macrophages can activate naïve CD4 cells, but not CD8 cells - DC have a harder time activating naïve CD8 cells DC need to be appropriately activated first: - infection, upregulation of co-stimulatory receptors - CD4 cell bound to same DC as the CD8 cells CD4 CD8 TCR:MHCpeptide Examples: DC HIV-specific CD8 T cells although viable, are not cytolytic or produce cytokines. Chronic LCMV infection in CD4-/- mice, CD8 T cells proliferate but no killing.

20 IV. Effector Functions of CD8+ Cytotoxic T Lymphocytes A. Ag-mediated Cytotoxicity defense against infected cells (viruses, cytoplasmic bacteria, some protozoan Toxoplasma gondii) tumor cells

21 Mechanisms of killing of infected cells by CD8+ cytotoxic T lymphocytes

22 - granules: initially formed when naïve CD8 T cell is primed replenished upon subsequent interaction preformed granules - quick release at synapse inactive in CTL - granules contain: perforin polymerizes, forming transmembrane pores through target cell membranes. the pores are cylindrical lipophilic outside, hydrophobic inside. allows water and salt (granzymes) to get into cell quickly. perforin on own is inefficient in killing. granzymes three+ proteases, digestive enzymes

23 Granzyme B cleaves pro-enzyme caspase 3 to active caspase 3 Caspase-3 degrades inhibitor of CAD (ICAD), bound to caspase-3-activated deoxyribonuclease (CAD) CAD is a endonuclease, degrades double stranded DNA (200-bp), responsible for DNA fragmentation that results in chromatin condensation. Granzyme B pro-caspase 3 ICAD CAD TUNEL assay. Granzyme B may degrade ICAD directly and caspases amply affect.

24 B. Fas-mediated apoptosis: - Killing of tumor cells/macrophage infected cells T cell FasL:Fas tumor cell - Quenching an immune response T cell FasL:Fas T cell - Tumor killing of T cells Tumor cell FasL: Fas T cell Nature Medicine 6, (2000)

25 C. CD8 cell cytokine production IFN-γ inhibits certain viral replication directly enhances - MHC class I and class II - adhesion and co-stimulatory molecules - Ag presenting capacity of macrophages TNF-α synergies with IFN-γ macrophage responses anti-viral

26 Cooperation between CD4 + and CD8 + cells in the eradication of intracellular infections Abbas & Lichtman, 2008

27 V. Resistance of Pathogenic Microbes to Cell-Mediated Immunity Factors in Infection Outcome Viral Pathology Outcome Immune Protection Immunopathology Viral induction of immunopathogenesis Martial Arts use your enemies strengths as their weakness. Pathogens use host immune systems to harm the host.

28 Types of Infection Outcomes 1. Protection with limited viral or immunopathology Viral Pathology Viral genetics Host Factors Immune System Induction Protection Immunopathology

29 2. Protection with considerable immunopathology Viral Pathology Induction Protection Immunopathology

30 3. Limited protection, considerable immunopathology Viral Pathology Induction Protection 1. Evasion Deregulation 2. Immunopathology

31 Evasion of cell-mediated immunity by microbes 1. Inhibition of lysosome digestion Abbas & Lichtman, 2008

32 Evasion of cell-mediated immunity by microbes 2. Inhibition of antigen presentation Abbas & Lichtman, 2008

33 Evasion of cell-mediated immunity by microbes 3. Cytokine deregulation - Chronic hepatitis B infection vs. resolved HBV infection high frequency of circulating CD4CD25Foxp3 Tregs Tregs correlated serum HBV DNA levels. Abbas & Lichtman, 2008

34 4. Latency (hiding) genetic function of virus eg. Herpesvirus: cytomegalovirus, EBV, herpes simplex virus 5. Antigenic escape (the disguise) - RNA viruses high mutation rate, error prone polymerase Hepatitis C Virus - Reverse Transcriptase higher mutation rate Lentivirus, HIV Polymerase Genome Rate/nucleotide Mutations/virus DNA 100 kb 1/ <1 RNA 10 kb 1/ >1 RT 10 kb <1/ Reverse Transcriptase highly error prone DNA polymerases proof reading functions

35 6. Antigenic shift (specialized disguise) - is the process by which two different strains of influenza combine to form a new subtype having a mixture of the surface antigens of the two original strains: Hemagglutinin (H) and Neruaminidase (N) - only occurs in influenza A, infects humans, birds, swine, horses, dogs H1N2 H5N2 + H5N1 Note: antigenic drift natural mutation overtime which could lead to viral escape. reassortment or viral shift - other viral systems or experimentally induced modified

36 Topics: I. Types of Cell-Mediated Immunity II. Migration of Effector T Lymphocytes to Sites of Infection III. Effector Functions of CD4+ Helper T Cells IV. Effector Functions of CD8+ Cytoxic T Cells V. Resistance of Pathogenic Microbes to Cell-Mediated Immunity