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T CELL MEDIATED IMMUNITY (Cell Mediated Immunity)

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Title: T CELL MEDIATED IMMUNITY (Cell Mediated Immunity)


1
T CELL MEDIATED IMMUNITY (Cell Mediated Immunity)
2
CELL MEDIATED IMMUNITY (CMI)
  • Adaptive immune response based on antigen
    specific T cells
  • Antigen specific T cells
  • CD8 (cytotoxic)
  • CD4 (helper)
  • TH1
  • TH2
  • Transfer to naïve recipient (operational
    definition)
  • Not with antiserum
  • Can with lymphoid cells (syngeneic donor and
    recipient)
  • Mature naïve T cells must be activated by
    specific antigen in secondary lymphoid tissues

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ACTIVATION OF NAÏVE T CELLS INTO EFFECTOR T CELLS
  • Purpose of secondary lymphoid tissues
  • Sites for initiation of adaptive response
  • Examples
  • Skin and soft tissues (SST) to regional lymph
    nodes
  • Blood stream to spleen
  • Respiratory mucosa to BALT and tonsils
  • Gastrointestinal mucosa to Peyers patches (GALT)
  • Dendritic cells important in SST infections
  • Immature
  • Phagocytic and migratory from infection sites
  • Mature
  • Interaction with T cells in 2nd lymphoid tissues

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ACTIVATION OF NAÏVE T CELLS INTO EFFECTOR T CELLS
  • Enter T cell zone of 2nd lymphoid tissue and
    encounter
  • Dendritic cells
  • Macrophages
  • Presentation of antigen
  • Activation into effector T cells
  • Effector cells
  • Remain in 2nd lymphoid tissue (CD4 TH2)
  • Travel to infection site (CD8 and CD4 TH1)
  • No encounter with specific antigen
  • Re-circulation to bloodstream

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HOMING OF T LYMPHOCYTES
  • Homing
  • Movement of naïve T cells into secondary lymphoid
    tissue or effector T cells to infection site
  • Homing determined by
  • Chemokines
  • CCL19 and CCL21
  • Cell adhesion molecules (CAMs)

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MOVEMENT OF T CELLS BY INTERACTION OF CAMS
  • Interaction (contact) is mediated by
  • Cell adhesion molecules (CAMs)
  • Cell adhesion molecules (CAMs)
  • On surface of leukocytes and target cells
  • Work independently of antigen
  • Direct specific cell to cell contact
  • Classification based on
  • Structure
  • CD nomenclature

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CLASSIFICATION OF CAMS ON STRUCTURAL BASIS
  • Selectins
  • Surface of leukocytes and macrophages
  • L selectin
  • Initiates interaction with endothelial cells
  • Vascular addressins
  • Surface of endothelial cells
  • GlyCAM-1 and CD34
  • Initiates interaction with leukocyte and
    macrophage selectins

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CLASSIFICATION OF CAMS ON STRUCTURAL BASIS
  • Integrins
  • Glycoproteins on surface of leukocytes and
    dendritic cells
  • Lymphocyte function associated antigen (LFA-1)
  • Initiates strong binding to
  • Immunoglobulin superfamily molecules
  • Intercellular adhesion molecules (ICAMs)
  • Strong binding allows T cells to squeeze between
    endothelial cells

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CLASSIFICATION OF CAMS ON STRUCTURAL BASIS
  • Immunoglobulin superfamily molecules
  • Located on leukocytes, APCs and endothelial
    cells
  • CD2, ICAM-1, ICAM -2
  • Initiates interaction with integrins
  • Various roles in cell adhesion
  • Passage of T cells between endothelial cells
  • LFA-1 to ICAMs
  • Interaction of T cells with APCs
  • CD2 to LFA-3

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ACTIVATION OF NAÏVE T CELLS REQUIRES
CO-STIMULATION
  • Antigen presenting cells (APCs) deliver both
  • Antigenic specific stimulation
  • Co-stimulation
  • Co-stimulation from professional APCs
  • Dendritic cells, macrophages, B lymphocytes
  • Co-stimulatory molecule is B7
  • B7 on APCs binds to CD28 on T cells

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CHARACTERISTICS OF PROFESSIONAL ANTIGEN
PRESENTING CELLS
  • Mechanism of antigen uptake
  • Expression of MHC molecules
  • Expression of B7
  • Antigens presented
  • Location in secondary lymphoid tissues
  • Location in body

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PHAGOCYTOSIS INDUCES CO-STIMULATORY ACTIVITY IN
MACROPHAGES
  • Resting macrophages express
  • No B7
  • Low level MHC II
  • Degradation of bacteria in phagolysosome release
    molecules which stimulate expression of B7 and
    MHC II
  • Lipopolysaccharide
  • Macrophages most commonly present antigens to CD4
    T cells
  • Listeria monocytogenes avoids MHC II presentation

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PHAGOCYTOSIS INDUCES MATURATION OF DENDRITIC CELLS
  • Immature dendritic cells present in skin and soft
    tissues
  • High level of phagocytosis and no co-stimulatory
    activity
  • Phagocytosis induces
  • Migration to lymphoid tissue
  • Maturation to mature dendritic cells
  • Interdigitating reticular cells
  • Expression of
  • B7, MHC I, MHC II, CCL18 and DC-SIGN
  • Dendritic cells stimulate CD4 and CD8 T cell
    responses

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ENDOCYTOSIS INDUCES B7 EXPRESSION IN B CELLS
  • Immunoglobulin receptors on B cells selective
    bind soluble protein antigen from extracellular
    environment
  • Lipopolysaccharide
  • Antigen / Immunoglobulin complex is internalized
    by
  • Receptor mediated endocytosis
  • Complexes delivered to endocytic vesicles
  • Degraded into peptides and bound to MHC II
  • Expression of B7
  • B cells present antigen to CD4 T cells

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ANTIGEN ACTIVATION OF T CELL RECEPTOR COMPLEX
INITIATES INTRACELLULAR SIGNALING PATHWAYS
  • Antigen binding transmits signal via CD3 and zeta
    proteins
  • Transmitted signal activates
  • Receptor associated kinases (Fyn)
  • Fyn leads to phosphorylation of ITAMs
  • Immunoreceptor tyrosine based activation motifs
    (ITAMs)
  • Cytoplasmic tails of CD3 and zeta proteins

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ANTIGEN ACTIVATION OF T CELL RECEPTOR COMPLEX
INITIATES INTRACELLULAR SIGNALING PATHWAYS
  • ZAP-70 (cytoplasmic tyrosine kinase) binds to
    phosphorylated ITAMs of zeta chain
  • Co-receptors (CD4 and CD8), with associated
    tyrosine kinase (Lck), bind to MHC molecules
  • Co-receptor binding to MHC allows Lck to
    phosphorylate and activate ZAP-70

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PROLIFERATION AND DIFFERENTIATION OF ACTIVATED T
CELLS BY INTERLEUKIN-2
  • Naïve T cells express low affinity IL-2 receptor
    consisting of beta and gamma chains only
  • Activation of naïve T cells induces
  • Synthesis and secretion of IL-2
  • Synthesis of IL-2 receptor alpha chain
  • Alpha chain combines with beta and gamma chains
    to make high affinity IL-2 receptor
  • IL-2 binds to receptor and initiates T cell
    proliferation

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ANTIGEN RECOGNITION BY NAÏVE T CELLS IN ABSENCE
OF CO-STIMULATION
  • Naïve T cell only activated by professional APC
    carrying specific peptideMHC complex and
    co-stimulatory molecule
  • T cell beomes anergic when it encounters APC
    carrying specific peptideMHC complex without
    co-stimulatory molecule
  • No effect on T cell which encounters APC carrying
    no specific peptideMHC complex but has
    co-stimulatory molecule

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EFFECTOR OPTIONS OF CD8 AND CD4 T CELLS
FOLLOWING ANTIGEN ACTIVATION
  • CD8 committed to becoming cytotoxic effector
    cells
  • CD4 T cells can differentiate along two pathways
  • TH1 (help with CMI)
  • TH2 (help with humoral immune response)
  • Mechanisms of differentiation not well understood
  • Most immune responses involve both TH1 and TH2

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CD4 T CELL RESPONSE TO MYCOBACTERIUM LEPRAE
  • Mycobacterium leprae is an intracellular
    pathogen, agent of leprosy and directs either TH1
    or TH2 response
  • Most effective immune response is mediated by TH1
    cells
  • Immune response mediated by TH1 cells results in
  • Tuberculoid leprosy
  • Immune response mediated by TH2 cells results in
  • Lepromatous leprosy

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Figure 6-21
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ACTIVATION OF NAÏVE CD8 T CELLS TO CYTOTOXIC
EFFECTOR CELLS
  • Activation of naïve CD8 cells requires strong
    co-stimulation
  • Dendritic cells provide strong co-stimulation
  • Express high levels of B7
  • APC with sub-optimal co-stimulation require CD4 T
    cell help
  • Naïve CD8 and CD4 cells must recognize specific
    antigen on on same APC

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ACTIVATION OF NAÏVE CD8 T CELLS TO CYTOTOXIC
EFFECTOR CELLS
  • Mechanisms of CD4 help
  • CD4 effector T cells secrete cytokines
    stimulating APC to increase level of B7
  • Naïve CD4 T cells secrete interleukin-2 which
    stimlates CD8 cells
  • Requirement for stronger co-stimulation of CD8
    cells means activation only when evidence of
    infection certain

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PERFORMANCE OF EFFECTOR T CELL FUNCTIONS
  • Classification of molecules which perform
    functions
  • Cytokines
  • Proteins made by cells and affect behavior of
    cells
  • Autocrine action
  • Paracrine action
  • Produced by all effector T cells
  • Cytotoxins
  • Proteins which kill target cells
  • Produced by cytotoxic CD8 cells

53
CYTOTOXINS AND CYTOKINES OF T CELLS
  • T cells are distinguished by
  • Cytokines and cytotoxins produced and the effects
    on immune response
  • CD4 T cells produce and act primarily through
    cytokines
  • Macrophage stimulating (TH1)
  • B cell activating (TH2)
  • CD8 T cells produce and act primarily through
    cytotoxins
  • Perforin and Granzymes

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SELECTIVE KILLING OF INFECTED CELLS BY CD8
CYTOTOXIC T CELLS
  • Cytotoxic CD8 kill by inducing apoptosis
  • Cells do not lyse or disintegrate but shrivel and
    shrink
  • Pathways of Apoptosis
  • Formation of transmembrane pores allowing
    proteolytic enzymes to enter
  • Perforin and granzymes cytotoxins
  • Induction of apoptosis signal following cell-cell
    binding
  • Fas ligand (CD8 T cell) to Fas receptor (Target
    cell)

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TH1 T CELLS AND MACROPHAGE ACTIVATION
  • Macrophage activation
  • Enhancement of macrophage function against
    intracellular pathogens by TH1 cells
  • Phagosome fused more efficiently with lysosome
  • Important with Mycobacteria
  • Activation of macrophages requires 2 signals
    provided by TH1 cells
  • Interferon-gamma
  • CD40 ligand

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INTRACELLULAR PATHOGENS AND GRANULOMA FORMATION
  • Mycobacteria can resist killing by activated
    macrophages resulting in formation of granulomas
  • Granulomas
  • Localized inflammatory response characterized by
  • Central core of infected macrophages surrounded
    by activated T cell
  • Central core of granuloma
  • Macrophages fused into multinucleated giant cells
    surrounded by large single macrophages
    (epithelioid cells)
  • In tuberculosis, centers of large granulomas
    display cheese-like appearance
  • Caseation necrosis

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TH2 T CELLS AND ACTIVATION OF B LYMPHOCYTES
  • CD4 TH2 cells activate B cells which recognize
    same antigen
  • Cognate interaction
  • Activation takes place in secondary lymphoid
    tissue
  • Mechanism
  • TH2 cell receptor binds to peptideMHC II complex
    on B cell
  • TH2 cell synthesizes
  • CD40 ligand which binds to CD40 receptor on B
    cell
  • Interleukin-4, interleukin-5, interleukin-6
  • Stimulate proliferation and differentiation of B
    cells

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KNOWLEDGE OF COGNATE INTERACTION IMPROVES VACCINE
DESIGN AND EFFICACY
  • Vaccination of infants and young children against
    Haemophilus influenzae type b
  • Haemophilus influenzae type b
  • Agent of invasive disease in children lt 5 years
  • Meningitis and epiglottitis
  • Prior to vaccine availability
  • Morbidity of 1 in 200 children
  • Mortality of 5
  • Approximately 70 of cases in children lt 18
    months
  • Major virulence factor is type b capsular
    polysaccharide

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KNOWLEDGE OF COGNATE INTERACTION IMPROVES VACCINE
DESIGN AND EFFICACY
  • 1980 vaccines consisted of
  • Purified type b capsular polysaccharide
  • Protects children gt 18 months
  • 1990 vaccines consisted of
  • Purified type b capsular polysaccharide
    conjugated to protein
  • ActHIB (Sanofi Pasteur)
  • Tetanus toxoid
  • HibTITER (Wyeth)
  • Diphtheria CRM 197 protein
  • Protects children gt 2 months

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