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    HAT HAS TO Happen TO Clear A Viral Infection

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    Stella Michelle Xu
    To clear a viral infection, the innate and adaptive immune responses must be coordinated. The innate response recognizes pathogens and activates adaptive immunity. The adaptive response involves T cells that recognize viral antigens presented by MHC molecules on antigen presenting cells. It also involves B cells that produce antibodies. Cytokines direct T cell differentiation into effector and memory cells. Both cellular and humoral immunity are required to clear the virus through immune effector mechanisms and generate immunological memory to mount a faster response upon re-exposure.

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    HAT HAS TO Happen TO Clear A Viral Infection

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    Stella Michelle Xu
    39 views57 pages
    To clear a viral infection, the innate and adaptive immune responses must be coordinated. The innate response recognizes pathogens and activates adaptive immunity. The adaptive response involves T cells that recognize viral antigens presented by MHC molecules on antigen presenting cells. It also involves B cells that produce antibodies. Cytokines direct T cell differentiation into effector and memory cells. Both cellular and humoral immunity are required to clear the virus through immune effector mechanisms and generate immunological memory to mount a faster response upon re-exposure.

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    Lecture - Adaptive

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    To clear a viral infection, the innate and adaptive immune responses must be coordinated. The innate response recognizes pathogens and activates adaptive immunity. The adaptive response involves T cells that recognize viral antigens presented by MHC molecules on antigen presenting cells. It also involves B cells that produce antibodies. Cytokines direct T cell differentiation into effector and memory cells. Both cellular and humoral immunity are required to clear the virus through immune effector mechanisms and generate immunological memory to mount a faster response upon re-exposure.

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    39 views57 pages

    HAT HAS TO Happen TO Clear A Viral Infection

    Uploaded by

    Stella Michelle Xu
    To clear a viral infection, the innate and adaptive immune responses must be coordinated. The innate response recognizes pathogens and activates adaptive immunity. The adaptive response involves T cells that recognize viral antigens presented by MHC molecules on antigen presenting cells. It also involves B cells that produce antibodies. Cytokines direct T cell differentiation into effector and memory cells. Both cellular and humoral immunity are required to clear the virus through immune effector mechanisms and generate immunological memory to mount a faster response upon re-exposure.

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    WHAT HAS TO HAPPEN TO CLEAR A VIRAL INFECTION??

    IMMUNE RESPONSES

    INNATE COMPONENT Recognition of PAMPs by PRRs Induction of the anti-viral state by Type1 IFNs NK cell activation and cytolysis Complement

    ADAPTIVE IMMUNITY

    COMPARISON OF INNATE AND ADAPTIVE IMMUNITY

    Goldsby, Immunology, 5th ed.

    INNATE AND ADAPTIVE IMMUNITY ARE BOTH


    REQUIRED FOR VIRAL CLEARANCE
    innate adaptive

    virus

    14

    21

    days Efficient response to an acute infection depends on coordination of both innate and adaptive responses

    THE ADAPTIVE (ACQUIRED) IMMUNE RESPONSE humoral response: actions of serum and lymph proteins cellular response: actions of specific helper and effector cells

    PLAYERS IN HUMORAL AND CELLULAR IMMUNITY

    Humoral

    Cellular

    Goldsby, Immunology, 5th ed.

    WHAT HAS TO HAPPEN TO CLEAR A VIRAL INFECTION?? 1. Recognize infection 2. Activate adaptive immune response
    a) T cells (Cellular)

    REQUIREMENTS TO INITIATE A T CELL RESPONSE Activation of T cells is a 3-step process 1. TCR/MHC/peptide recognition
    2. Co-stimulatory signals
    T cell: CD28 APC: B7 (CD80/86

    3. Cytokine mediated differentiation

    IMPORTANT RECEPTORS ON T CELLS


    Th: Helper T cell Tc: Cytotoxic T cell

    TCR: T cell receptor CD4: co-receptor (MHCII) CD8: co-receptor (MHCI)

    Goldsby, Immunology, 5th ed.

    TCRS RECOGNIZE PEPTIDE PRESENTED BY MHC

    ANTIGEN PRESENTATION MHC I presents endogenous antigen proteins synthesized in an infected cell - CD8 T cell restricted

    MHC II presents exogenous antigens proteins or antigens endocytosed from outside the cell - CD4 T cell restricted

    ANTIGEN PRESENTING CELLS (APCs)


    Cells presenting both MHC I and MHC II: Dendritic cells macrophages B-cells

    Cells presenting MHC I: all nucleated cells

    ANTIGEN PRESENTING CELLS


    - - - - Dendritic cells, macrophages, B cells" Immature APCs patrol tissues and collect antigen" Rapidly recognize danger through expression of PRRs" Mature APCs migrate to lymphoid organs and activate specic T cell response" - Bridge between innate and adaptive immunity"

    ANTIGEN PRESENTATION MHC I presents endogenous antigen proteins synthesized in an infected cell - CD8 T cell restricted

    AG PRESENTATION BY MHC CLASS I (infected cell)


    cytosol

    cell surface

    TAP transporter

    MHC class I

    cytosol

    AG CROSS-PRESENTATION BY MHC CLASS I (APC)

    Immunology and Cell Biology (2008) 86, 353362

    ANTIGEN PRESENTATION

    MHC II presents exogenous antigens proteins or antigens endocytosed from outside the cell - CD4 T cell restricted

    AG PRESENTATION BY MHC CLASS II (APC)

    Ag

    MHCII

    IMPORTANCE OF CO-STIMULATORY MOLECULES Activation of T cells is a 3-step process


    1. TCR/MHC/peptide recognition

    2. Co-stimulatory signals
    T cell: CD28 APC: B7 (CD80/86)

    3. Cytokine mediated differentiation

    DENDRITIC CELL MATURATION: REQUIREMENT FOR CO-STIMULATION


    Immature DC No B7 expression Low MHCII expression Mature DC B7 expressed High MHCII expression

    Adapted from Nature Reviews Immunology 4, 24-35 (January 2004)

    Co-stimulation is essential for differentiation of effector T cells

    EFFECTOR CTL KILLING: GRANZYMEB AND PERFORIN

    Goldsby, Immunology, 5th ed.

    GRANZYMEB MEDIATED TARGET CELL KILLING USES PERFORIN

    Goldsby, Immunology, 5th ed.

    ROLE OF CD4 T CELLS

    Nave CD4+ Th0 Effector Th1 OR Th2 (balance determines disease outcome) Memory CD4 T cells

    Goldsby, Immunology, 5th ed.

    help for CTLs via cytokines

    CD8

    TCR/CO-STIM ACTIVATION OF CD4 TH CELLS

    IL-2 signals from nearby Th1 cells help CTL differentiation and proliferation
    Goldsby, Immunology, 5th ed.

    CYTOKINE MEDIATED T CELL DIFFERENTIATION Activation of T cells is a 3-step process


    1. TCR/MHC/peptide recognition 2. Co-stimulatory signals
    T cell: CD28 APC: B7 (CD80/86)

    3. Cytokine mediated differentiation

    BALANCE BETWEEN CELLULAR (TH1) AND HUMORAL (TH2) RESPONSES


    TH1 TH2

    BALANCE BETWEEN CELLULAR (TH1) AND HUMORAL (TH2) RESPONSES


    TH1 TH2

    BALANCE BETWEEN CELLULAR (TH1) AND HUMORAL (TH2) RESPONSES


    TH1 TH2

    BALANCE BETWEEN CELLULAR (TH1) AND HUMORAL (TH2) RESPONSES


    TH1 TH2

    BALANCE BETWEEN CELLULAR (TH1) AND HUMORAL (TH2) RESPONSES


    TH1 TH2

    REQUIREMENTS FOR INITIATING A T CELL RESPONSE Activation of T cells is a 3-step process


    1. TCR/MHC/peptide recognition
    APCs present multiple peptides T cells specifically recognize unique non-self peptide T cell: CD28 APC: B7 (CD80/86) Co-stim signals NECESSARY for T cell priming, proliferation and acquisition of effector function Determines TH1 versus TH2 response

    2. Co-stimulatory signals

    3. Cytokine mediated differentiation

    WHAT HAS TO HAPPEN TO CLEAR A VIRAL INFECTION?? 1. Recognize infection 2. Activate adaptive immune response
    a) T cells b) B cells (Humoral)

    HUMORAL IMMUNITY

    Goldsby, Immunology, 5th ed.

    ANTIBODIES

    B CELL ACTIVATION

    IL-4

    help for B-cells via cytokines

    B CELL ACTIVATION ALSO REQUIRES A SECOND


    SIGNAL
    1 - Ag/Ab cross-linking

    2 - CD40/CD40L interaction with Th cell

    Janeway, Immunobiology, 6th ed.

    IL-4/CD40

    IL-5/IL-6

    ROLE OF B CELLS/HUMORAL IMMUNITY IN VIRAL


    INFECTION
    Can be localized to infection site and inhibit infection
    IgA in mucosal secretions Inhibition of viral attachment Inhibiton of viral entry

    Opsonization Complement mediated lysis (enveloped)

    CELLULAR AND HUMORAL IMMUNITY - Putting it all together

    WHAT HAS TO HAPPEN TO CLEAR A VIRAL INFECTION??

    WHAT HAS TO HAPPEN TO CLEAR A VIRAL INFECTION??

    LYMPHOCYTE CLONAL EXPANSION AND MEMORY


    GENERATION

    Goldsby, Immunology, 5th ed.

    VIRAL CLEARANCE AND GENERATION OF MEMORY


    T cells NK cells virus Ab
    IgM IgG

    weeks
    Efficient response to an acute infection involves innate, cellular and humoral responses

    ADAPTIVE RESPONSE RESULTS IN GENERATION OF


    MEMORY

    Memory is specific and results in more robust response with subsequent exposure
    Goldsby, Immunology, 5th ed.

    WHY IS MEMORY BETTER? Higher frequency of Ag specific T and B cells Primed for quick response Memory T cells do not require co-stimulation for activation Tissue localization

    Adaptive response: pliable, flexible Multiple antigens presented on a single APC Single lymphocyte = monospecific response

    Clonal selection and expansion of virus-specific B and T cells The host repertoire: genetic differences Recognition of antigen: specific, pluripotent Amplification of virus specific cells Somatic mutation in B cells: refinement Immune memory

    Specific recognition of Antigen Clearance of Antigen Memory of Antigens

    PATTERNS OF INFECTION AND THEIR RELATIONSHIP


    TO IMMUNE DEFENSES

    ACUTE INFECTION AND CLEARANCE OF VIRUS


    CTLs

    virus Ab

    weeks Brief course; virus eliminated within days.

    PERSISTENT INFECTION

    virus Ab CTLs weeks No clearance of virus, lack of immune response Ex: measles/SSPE, arenaviruses

    LATENT INFECTION
    1) Acute infection 2) Immune reactivation and apparent clearance 3) Virus goes into hiding herpesvirus: latency in neurons 4) Virus is reactivated at later time.

    SLOW INFECTION
    Hallmarks: very slow replication Low/no immune response Ex: Scrapie, Kuru, Bovine Spongiform Encephalopathy

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