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