Download Cell-cell-interactions

Cell-cell interactions in
immune responses
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
Cell-cell interactions
• Immune cells interact in two ways
– Direct contact between cells
– Cytokine signaling acting in autocrine or paracrine
fashion
Central role of Th cells
• Type of immune
response:
APC
MHC
– B activation or
CTL generation
Ag
TCR
B cell
Th
cell
T0 cell
Cytokines
Eosinophil Macrophage
NK cell
K cell
Cytokines
• Proliferation of
effector cells
• Enhance
functional
activities of other
cells
Subpopulations of Th cells
• Subpopulations based on cytokine profiles
– Th0, Th1, Th2, Th17
• Differentiation determined by cytokines
preTh
Th0
IL-2
IFN-γ, IL-2,
IL-4, IL-5,
IL-10
IL-12
Th1
IFN-γ, IL-2
Th2
IL-4, IL-5,
IL-6, IL-10
Th17
IL-17
Subpopulations of Th cells
• Th1 cytokines
Th1
IFN-γ
IL-2
Activates
Th2
IL-10 inhib productn IL-10
IL-5
IL-6
IL-4
– Activate macrophages
– Enhance generation of
CTL
– inflammation
• Th2 cytokines
Activates
Macrophage
Eosinophil
B cell
Ab production
Mast cell
– Activate B cells
– Activate granulocytes
– Ab-mediated immune
response
Subpopulations of Th cells
Th1
IFN-γ
IL-2
Activates
Th2
• Regulation
IL-10 inhib productn IL-10
IL-5
IL-6
IL-4
Activates
Macrophage
Eosinophil
B cell
Ab production
Mast cell
– Ag
– IFN-γ inhibits
proliferation of Th2 cells
& differentiation of Th17
– IL-10 inhibits production
of IFN-γ
– IL-4 inhibits production
of Th1 & differentiation
of Th17
Cell-cell interactions in
Ab responses
Responses to exogenous Ag
T-dependent Ag
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
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
CD40
BCR
B cell
MHC
1.
Hapten binds BCR
Endocytosed
Ag presented
BCR
B cell
MHC
Ag
TCR
CD28
CD80/86
2. CD80 expressed
Thcell
Mechanism of hapten-carrier effect
• Activated Th2 produce cytokines and CD40L
• CD40L interacts with CD40 = signal 2
• Cytokines drive proliferation and
differentiation of Bs
CD40L
4.
BCR
B cell
MHC
Ag
TCR
Th cell
Cytokine binds R
CD40L binds CD40
Bs activation
BCR
BCR
BCR
B cell
B cell
B cell
CD28
3.
CD80/86
Th activated,
express CD40L,
cytokine release
5.
cytokines
B cell proliferate,
differentiate,
secrete Ig
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
1.
APC
MHC
CD80/86
Ag
TCR
CD28
Th cell
Th primed
by APC
BCR
B cell
MHC
Ag
TCR
CD28
CD80/86
Th cell
Th signals B
2. Bs proliferate,
differentiate,
secrete Ig
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
Cytokines and class switching
• Th cell cytokines stimulate B cell proliferation
and differentiation
• Cytokines also regulate the class of Ab
Cytokine
IgG1 IgG2a
IL-4
↑
IgG2b IgG3
↓
↓
IL-5
IFN-γ
TGF-β
IgA
IgE
IgM
↑
↓
↓
↓
↑
↓
↑
↑
↑
↓
↑
↓
Cell-cell interactions in
Ab responses
Responses to exogenous Ag
T-independent Ag
Cell-cell interactions in response to
T-independent Ag
• Cell-cell interactions do not occur
• Activation of Bs without class II self MHCrestricted T help
• Polymeric nature of these Ags allows for crosslinking of Ag receptors on Bs
• No 2° response, affinity maturation, or switch
• Response dominated by CD5+ Bs
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
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
Cell-cell interactions in
cell-mediated immune response:
Generation of CTL
Responses to endogenous Ag in cytosol
Killing of virus-infected and transformed cells
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”
Generation of CTL
• Differentiate in
response to:
stimulator
MHC
Class I
1.
Stimulator cell
presents Ag in
MHC class I to
CD8+ pre-CTL
– Specific Ag in MHC
– Cytokines from Th1 Ts
Ag
TCR
CD28
CD8+
pre-CTL
CD4+
Th cell
TCR
3.
Pre-CTL
differentiates to
functional CTL
cytokines
Th releases
IFN-γ, IL-2
Ag
CD80/86
MHC
Class II
APC
2.
APC presents Ag
in MHC II to
CD4+ Th cell
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
Mechanisms of CTL killing
• Fas and TNFmediated 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
Mechanisms of CTL killing
• CTL granulemediated killing
– perforin &
granzymes
released from
CTL granules
– Perforin
polymerizes and
forms channels in
membrane
– Granzymes
(serine proteases)
enter through
channel, activate
caspases
Cell-cell interactions in cellmediated immune response:
activation of macrophages
Responses to endogenous Ag in vesicles
Killing of intracellular pathogens in vesicles
Central role of macrophage in
specific immune response
Infecting
agent
• Initial defense
Macrophage
– Innate, nonspecific
immune response
cytokines
• Ag presentation
Ag presentation
Macrophage
Activated macrophage
Macrophage
MHC
Class II
Ag
TCR
Cytokines
Anti-microbial
Anti-tumor
T cell
lymphokines
– Activation of Th
• Effector functions
– Cytokine production
– Anti-microbial
– Anti-tumor
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