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Cell-Mediated Immunity (T cell differentiation signal 3 (CD4+ T cell…
Cell-Mediated Immunity
T cell differentiation
signal 3
CD4+ T cell
Th17
Ex. extracellular bacteria and fungi (PAMP-PRR)
involved in autoimmunity
Tfh
Ex. involved in B cell activation
Th2
Ex. parasites, extracellular pathogen (PAMP-PRR)
involved in allergy
Treg
Th1
Ex. viral infection (PAMP-PRR)
CD8+ T cell
CTLs
different PAMP-PRR interaction
different signal 3 cytokines
released from APC
trigger
different differentiation of T cells
by
different transcriptional factors in T cell
Stat proteins
different TFs in T cell activate
different master transcriptional regulators
different T cell subtypes
different effector functions
different effector cytokines
general expression
on effector T cells
Fas ligand
CTLs & Th1
binds Fas on infected cells
CD40 ligand
T helpers
except Treg
binds CD40 on B cells or other immune cells
as activation signal
cross regulation
by cytokine profile
IF-12/IFN-𝜸
:
Th1↑
& Th2↓
IL-4
:
Th2↑
& Th1↓
IL-4/IFN-𝜸
:
Th17↓
by master transcriptional regulator
T-bet: Th1↑ & Th2↓
GATA3: Th1↓ & Th2↑
decision point
TGF-𝜷
Th17/Treg
inflammation state
:
IL-6↑
:
Th17↑
by ROR𝜸t dominance
normal state
:
Treg↑
suppress inflammation
homing
different cell surface molecules
on naive and effector T cells
cell surface molecules on effector T cells
target them to site of infection
CD8+ T cell activation
require more costimulation
IL-2 can be from Th1 or Th17
activation
involve cross-presentation
sequential activation
APC is licensed by CD4+ via CD40L
licensed APC interact with CD8+ indenpendently
IL-2 from only CD8+
simultaneous activation
APC is licensed by CD4+ via CD40L
during licensing, APC also interact with CD8+
IL-2 from both CD4+ and CD8+
memory CD8+ always require CD4+ help
CTL effector function
kill infected cells
by inducing apoptosis
FasL-Fas
FasL on CTL
Fas on infected cell
trigger signaling cascade
cleavage of procaspase to caspase
granules
after TCR:pMHC-I recognition
reorganization of cytoskeleton
to release granules
at point of cell contact
granule content
perforin
pore-forming protein
granzyme
serine protease
granzyme B
enter cytosol through
perforin pore to trigger apoptosis
initial interaction via
non-specific adhesion molecules
recognition of
pMHC-I antigen presentation
granule
FasL-Fas interaction
one CTL can kill multiple infected cells
secrete cytokines
to direct immune response
secrete
IFN-𝜸
(type II IFN)
increase MHC-I expression
increase matching chance
activates and recruit macrophage
Th1
signal 3 cytokines
IL-12
IFN-𝜸
effector cytokine
IFN-𝜸
master transcriptional regulator:
T-bet
Th1 effector function
macrophage activation by IFN-𝜸
(CTL also secrete IFN-𝜸)
boost antimicrobial activity
boost production of TNF-𝜶 in macrophage
activated M1 macrophage
increased expression of
MHC-II
CD40, B7 molecules, IL-12
CTL activation and differentiation
kill infected cell
Ex. chronically infected macrophage
FasL on Th1
apoptosis
help CD8+ activation
IL-2 secretion (paracrine)
stimulate differentiation of monocyte
in bone marrow
IL-3 and GM-CSF
(endocrine effect)
change adhesion molecule expression
on neighboring endothelial cells
to recruit more macrophages
Th1 cytokines
macrophage recruitment
Th1 chemokines
response to
intracellular organism
intracellular bacteria & protozoa
M. tuberculosis
in
lung macrophage infection
resist antimicrobial effect
of macrophage
chronic infection
in lung macrophage
formation of granuloma
core of infected macrophage
forming large multi-nucleated cells
become
necrotic
surrounded by
activated macrophages
and
Th1 cells
expression of CD40L