CellCell Interactions in Immune Responses

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Cell-Cell Interactions in Immune Responses
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Cell-Cell Interactions

• Cells of the immune system interact in two ways
• Direct contact between cells
• Via cytokines acting in a autocrine or paracrine
  fashion

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Central Role of Helper T cells

• Determine type of immune response
• B cell activation
• Tc cell generation
• Proliferation of effector cells
• Enhancement of functional activities of other
  cells

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Subpopulations of Th Cells

• Subpopulations based on cytokine profiles
• Th0
• Th1
• Th2
• Differentiation determined by cytokines
• Influenced by antigen
• IL-4 - Th2 cells
• IL-12 Th1cells

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Subpopulations of Th Cells

• Th1 cell cytokines
• Activate macrophages
• Generation of Tc
• Th2 cell cytokines
• Activate of B cells
• Activate granulocytes

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Subpopulations of Th Cells

• Regulation
• Antigen
• INF-? inhibits proliferation of Th2 cells
• IL-10 inhibits production of INF-?

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Cell-Cell Interactions in Antibody Responses

• Responses to Exogenous Antigens
• T-dependent antigens

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Hapten-Carrier Effect

• Studies on the antibody response to
  hapten-carrier conjugates showed that both T
  cells and B cells were required for antibody
  production
• Th cells recognize carrier determinants
• B cells recognize haptenic determinants
• Interactions are class II self-MHC restricted
• B cells function in antigen recognition and
  antigen presentation

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Mechanism of Hapten-Carrier Effect

• Hapten recognized by Ig receptor on B cell
  (Signal 1)
• Hapten-carrier endocytosed and processed
• Carrier determinants presented in association
  with class II MHC to Th2 cell
• Activated Th cells produce cytokines and CD40
  ligand
• CD40 ligand interacts with CD40 to activate B
  cell (Signal 2)
• Cytokines drive proliferation and differentiation
  of B cells to produce anti-hapten antibodies

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Cell-Cell Interactions in Primary Antibody
Response

• B cells are not the best APC in primary Ab
  response
• Dendritic cells
• Macrophages
• Th cells can be primed by other APCs before
  interaction with B cells

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B cell takes up and presents antigen
Th cells are primed by antigen-presenting cell
B-T cell cooperation B cells receive signals from
T cells
B cells divide
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Cell-Cell Interactions in Secondary Antibody
Responses

• Memory B cells and memory T cells created during
  primary response
• B cells have high affinity Ig receptors
• Can take up antigen at much lower concentrations
  than other APCs that lack Ig receptors
• Memory T cells are more easily activated than
  naïve T cells
• B-T cell interaction is sufficient to generate
  secondary antibody responses

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Cytokines and Class Switching

• Th cell cytokines not only stimulate
  proliferation and differentiation of B cells
• Cytokines also help regulate the class of
  antibody produced

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Cytokines and Class Switching
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Cell-Cell Interactions in Antibody Responses

• Responses to Exogenous Antigens
• T-Independent antigens

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Cell-Cell Interactions in Response to
T-independent Antigens

• Cell-cell interactions do not occur
• Activation of B cells without class II self
  MHC-restricted T cell help
• Polymeric nature of these antigens allows for
  cross-linking of antigen receptors on B cells
  resulting in activation
• No secondary response, affinity maturation or
  class switching
• Response dominated by CD5 B cells

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CD5 B cells

• CD5 B cells (B1 cells) are a population of B
  cells distinct from conventional B cells (B2
  cells)
• Properties
• First to appear in ontogeny
• Express surface IgM but little or no IgD
• Produce primarily IgM antibodies from minimally
  mutated germline genes
• Antibodies are of low affinity and can bind
  multiple antigens (polyreactive)
• Account for most of the IgM in adult serum

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CD5 B cells

• Properties (continued)
• Do not develop into memory cells
• Self-renewing (do not continue to arise form bone
  marrow and conventional B cells)
• Reside in peripheral tissues
• Predominant B cells in peritoneal cavity
• Significance
• Major defense against many pathogens that have
  polysaccharides in their cell walls
• Individuals with T cell defects can still resist
  many bacterial infections

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Cell-Cell Interactions inCell-Mediated
ImmunityGeneration of Cytotoxic T cells

• Responses to Endogenous Antigens in Cytosol
• Killing of virus infected and tumor cells

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Cytotoxic T cells (CTLs)

• CTLs are not fully mature when they exit the
  thymus
• Have a TCR that recognizes antigen in association
  with class I MHC molecules
• Cannot kill
• Called pre-CTL
• Must differentiate into fully active CTL

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Generation of CTLs

• Differentiate in response to two signals
• Specific antigen associated with class I MHC
  molecules
• Cytokines produced by Th1 cells

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Features of CTL Killing

• Antigen specific
• Target cell must bear the same antigen associated
  with class I MHC as did the pre-CTL
• Requires cell contact
• Ensures that nearby cells are not killed
• CTLs are capable of killing many targets
• CTLs are not injured when they kill a target

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Mechanisms of CTL Killing

• Tc kill using a variety of mechanisms
• Direct cell-cell contact via surface molecules
• Indirect signaling via cytokines

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Mechanisms of CTL Killing

• Fas and TNF-mediated killing
• Fas-L induced on CTL interacting with Fas
  receptor on target cell
• TNF secreted by CTL interacting with TNFR on
  target cell

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Mechanisms of CTL Killing

• Fas and TNF-mediated killing
• Binding of ligand results in tirmerization of the
  receptor
• Receptors with death domains activate caspases
  resulting in apoptosis

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Mechanisms of CTL Killing

• CTL granule-mediated killing
• Granules containing perforin and granzymes are
  released by CTL
• Perforin polymerizes and forms channels in target
  cell membrane
• Granzymes (serine proteases) enter through
  channels and activate caspases resulting in
  apoptosis

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Mechanism of CTL Killing
Tc cell
Tc cell
Granzymes
Perforin monomers
Ca
Perforin polymerizes
Polyperforin channels
Target cell
Target cell
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Steps in CTL Killing
1. Tc recognizes antigen on target cell
Tc cell
Target cell
Target cell
3. The Tc detaches from the target cell
Tc cell
Target cell
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Cell-Cell Interactions inCell-Mediated
ImmunityActivation of Macrophages

• Responses to Endogenous Antigens in Vesicles
• Killing of intracellular pathogens in vesicles

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Central Role of Macrophages in Specific Immunity

• Initial defense
• Non-specific Immunity
• Antigen presentation
• Activation of Th cells
• Effector functions
• Cytokine production
• Anti-microbial
• Anti tumor

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Detailed Functions of Macrophages
Inflammation Fever, Production of IL-6,
TNF-alpha, IL-1 act as pyrogen
Damage to tissues Hydrolases, Hydrogen peroxide
production Complement C3a TNF alpha production
Immunity Selection of lymphocytes to be
activated IL-12 results in Th1 activation IL-4
results in Th2 activation Activation of
lymphocytes Production of IL-1 Processing and
presentation of antigen
Antimicrobial action O2dependent production of
hydrogen peroxide, superoxide, hydroxyl
radical, hypochlorous acid O2-independent
production of acid hydrolases, cationic
proteins, lysozyme
Anti-tumor activity produced by Toxic
factors Hydrogen peroxide Complement
C3a Proteases, Arginase Nitric oxide TNF alpha
Reorganization of tissues, Secretion of a variety
of factors Degradative enzymes (elastase,
hyaluronidase, collagenase) Fibroblast
stimulation factors Stimulation of angiogenesis
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Macrophage Activation

• Many effector functions of macrophages are only
  performed following activation
• Two ways to activate macrophages
• IFN-? produced by Th1 cells plus bacterial
  products (endotoxin LPS)
• IFN-? produced by Th1 cells plus TNF-a produced
  by macrophages

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Mechanisms of Macrophage Activation
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Examples of Protection by Activated Macrophages

• Pneumocystis carinii, an extracellular fungal
  pathogen is controlled in normal individuals by
  activated macrophages however, in AIDS patients
  that are T cell deficient it is a common cause of
  pneumonia and death
• Mycobacterium tuberculosis, an intracellular
  pathogen that resides in vesicles, is not
  efficiently killed by macrophages unless they are
  activated hence this infection is a problem in
  AIDS patients

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Macrophage Effector Mechanisms

• TNF-a production (apoptosis)
• Nitric oxide and other reactive nitrogen
  intermediates (RNI)
• Reactive oxygen intermediates (ROI)
• Cationic proteins
• Hydrolytic enzymes
• ADCC

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Cell-Cell Interactions inCell-Mediated
ImmunityActivation of NK cells

• Killing of virus infected and tumor cells

No Direct Th cell/NK cell contact
needed Cytokines (IL-2 and IFN-?) from Th cells
activated by APCs activate NK cells
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NK cells

• Derived from bone marrow
• Large Granular Lymphocytes (LGLs)
• Lack most T and B cell markers (no TCR or BCR)
• No thymic maturation
• Express CD56, CD16 and Fc receptor for IgG and
  lack CD3
• Cytokines (IL-2 and INF-?) produced by Th1 cells
  promote differentiation into lymphokine activated
  killer cells (LAK cells)
• Kill virus infected and tumor cells, particularly
  LAK cells)

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NK and LAK Effector Mechanisms

• Similar to CTLs
• Not MHC restricted
• Susceptibility of target cell to killing is
  inversely proportional to expression of class I
  MHC
• Killer inhibitory receptors (KIRs) on NK and LAK
  cells recognize class I MHC and prevent killing
• Tumor and virus infected cells down-regulate
  class I MHC

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NK and LAK Effector Mechanisms

• IgG-coated target cells are recognized by Fc
  receptor and can be killed by ADCC
• LAK cells have a broader target cell range than
  do NK cells