Cellcell interactions in immune responses

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Cell-cell interactions inimmune responses

• Jennifer Nyland, PhD
• Office Bldg1, Room B10
• Phone [phone]
• Email jnyland_at_uscmed.sc.edu

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Teaching objectives

• To discuss the central role of Th cells in immune
  responses
• To describe the cell-cell interactions which
  occur in 1) Ab responses to T-dependent Ag, 2)
  generation of CTL, 3) activation of macrophages
  and NK cells
• To discuss responses to T-independent Ag
• To discuss mechanisms of killing by CTL and
  macrophages

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Cell-cell interactions

• Immune cells interact in two ways
• Direct contact between cells
• Cytokine signaling acting in autocrine or
  paracrine fashion

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Central role of Th cells

• Type of immune response
• B activation or CTL generation
• Proliferation of effector cells
• Enhance functional activities of other cells

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Subpopulations of Th cells

• Subpopulations based on cytokine profiles
• Th0, Th1, Th2, Th17
• Differentiation determined by cytokines

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Subpopulations of Th cells

• Th1 cytokines
• Activate macrophages
• Enhance generation of CTL
• inflammation
• Th2 cytokines
• Activate B cells
• Activate granulocytes
• Ab-mediated immune response

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Subpopulations of Th cells

• Regulation
• Ag
• IFN-? inhibits proliferation of Th2 cells
  differentiation of Th17
• IL-10 inhibits production of IFN-?
• IL-4 inhibits production of Th1 differentiation
  of Th17

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Cell-cell interactions inAb responses

• Responses to exogenous Ag
• T-dependent Ag

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Hapten-carrier effect

• Studies on Ab response to hapten-carrier
  conjugates show
• Both Ts and Bs required for Ab production
• Th cells recognize carrier determinants
• Bs recognize haptenic determinants
• Interactions are class II self MHC restricted
• Bs function in Ag recognition and presentation

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Mechanism of hapten-carrier effect

• Hapten recognized by BCR signal 1
• Hapten-carrier endocytosed and processed
• Carrier determinants presented in context of MHC
  class II to Th2 cells

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Mechanism of hapten-carrier effect

• Activated Th2 produce cytokines and CD40L
• CD40L interacts with CD40 signal 2
• Cytokines drive proliferation and differentiation
  of Bs

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Cell-cell interactions in 1 Ab response

• Bs are not best APC in 1 Ab response
• DC and macrophage
• Th cells can be primed by other APC before
  interaction with Bs

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Cell-cell interactions in 2 Ab response

• Memory Bs and memory Ts created during 1
  response
• Bs have high affinity Ig receptor
• Can take up Ag at lower concentrations than other
  APCs that lack Ig R
• Memory Ts more easily activated than naïve
• B-T interaction is sufficient to generate 2 Ab
  response

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Cytokines and class switching

• Th cell cytokines stimulate B cell proliferation
  and differentiation
• Cytokines also regulate the class of Ab

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Cell-cell interactions inAb responses

• Responses to exogenous Ag
• T-independent Ag

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Cell-cell interactions in response
toT-independent Ag

• Cell-cell interactions do not occur
• Activation of Bs without class II self
  MHC-restricted T help
• Polymeric nature of these Ags allows for
  cross-linking of Ag receptors on Bs
• No 2 response, affinity maturation, or switch
• Response dominated by CD5 Bs

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CD5 B cells

• CD5 Bs (B1 cells)
• Distinct from conventional Bs (B2 cells)
• First to appear in ontogeny
• Express surface IgM, little or no IgD
• Produce IgM from minimally mutated germline
• Ab are low affinity and polyreactive
• Account for most of IgM in adult serum

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CD5 B cells

• Properties (continued)
• Do not develop into memory Bs
• Self-renewing do not continue to arise from bone
  marrow like conventional Bs
• reside in peripheral tissues
• Predominant Bs in peritoneal cavity
• Significance
• Major defense against pathogens with
  polysaccharide in cell wall
• Individuals with T defects can still resist many
  bacterial infections

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Cell-cell interactions incell-mediated immune
responseGeneration of CTL

• Responses to endogenous Ag in cytosol
• Killing of virus-infected and transformed cells

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Cytotoxic T cells

• CTLs are not fully mature when exit thymus
• TCR recognizes Ag in MHC context
• Cannot kill
• Must differentiate to fully active CTL
• Therefore, are pre-CTL

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Generation of CTL

• Differentiate in response to
• Specific Ag in MHC
• Cytokines from Th1 Ts

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Features of CTL

• Ag specific
• Target must bear the same Ag in MHC class I as
  the stimulator cell
• Requires cell contact
• Ensures that nearby cells are not killed
• CTLs are capable of killing many targets
• They are not damaged when they kill a target

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Mechanisms of CTL killing

• Fas and TNF-mediated killing
• FasL on CTL binds FasR
• TNF secreted by CTL binds TNFR on target
• L binding trimerizes R
• R with death domain activates caspases to signal
  apoptosis

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Mechanisms of CTL killing

• CTL granule-mediated killing
• perforin granzymes released from CTL granules
• Perforin polymerizes and forms channels in
  membrane
• Granzymes (serine proteases) enter through
  channel, activate caspases

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Cell-cell interactions in cell-mediated immune
response activation of macrophages

• Responses to endogenous Ag in vesicles
• Killing of intracellular pathogens in vesicles

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Central role of macrophage inspecific immune
response

• Initial defense
• Innate, nonspecific immune response
• Ag presentation
• Activation of Th
• Effector functions
• Cytokine production
• Anti-microbial
• Anti-tumor

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Effector function of activated macrophages

• Pneumocystis carinii
• Extracellular fungal pathogen
• Controlled by activated macrophage
• In AIDS patients infection commonly causes death
• Mycobacterium tuberculosis
• Intracellular pathogen, resides in vesicles
• Not killed unless macrophages are activated
• Again, problem for AIDS patients