T CELL MEDIATED IMMUNITY (Cell Mediated Immunity)

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T CELL MEDIATED IMMUNITY (Cell Mediated Immunity)
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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

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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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