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Linkage between Innate and Adaptive Immunity (signaling (adaptor &ā¦
Linkage between
Innate and Adaptive
Immunity
APC
professional APC
DCs, macrophages, activated B cells
express
costimulatory molecules
when activated
initiate
signal 2
(
survival signal
)
express both
MHC-I & MHC-II
non-professional APC
all nucleated cells
no costimulatory molecule
express
MHC-I
(no MHC-II in normal conditions)
Antigen Presentation
generation of pMHC
MHC-I
endogenous
antigen presentation
endogenous peptides
in cytoplasm
ubiquitination
of endogenous peptides
proteasome
for degradation
degraded
peptide fragments
in cytoplasm
TAP
brings
peptide fragments
into ER
partially folded
MHC-I š¶ chain
by a chaperone (
calnexin
)
MHC-I š¶ chain + š· immunoglobulin
after released by
calnexin
partially folded MHC-I
to
TAP
by
tapasin
TAP
brings
peptide fragments
into ER
pMHC-I
released
from
TAP
pMHC-I
transported to
cell membrane
MHC-II
exogenous
antigen presentation
exogenous peptides
uptake
by endocytosis or phagocytosis
acidification of endosome
proteolytic activity
degraded
peptide fragments
in endosome
peptide fragment endosome joins
MHC-II + CLIP complex endosome
MHC-II loading complex
HLA-DM
releases
CLIP
from
MHC-II
peptide fragment binds to MHC-II =
pMHC-II
pMHC-II
transported to
cell membrane
complete
MHC-II
in ER
MHC-II
controlled by
invariant chain
(li)
transport guidance, prevent peptide binding
sorting signal in cytoplasmic tail of li
MHC-II, li complex
transported
to endosome
acidification of endosome
proteolytic activity
(invariant chain cleaved)
MHC-II + CLIP complex
in endosome
peptide fragment endosome joins
MHC-II + CLIP complex endosome
MHC-II loading complex
exceptions
endogenous peptide by MHC-II
endogenous antigen presented by MHC-II
via
autophage
endogenous peptides in
autophagosome
fuse with MHC-II loading complex
DC present antigen with MHC-II
activation of CD4+ T cell
allorecognition
T cell recognize peptide bound with
non-self MHC
1-10% of T cell can react to allogenic MHC
main mechanism of avoid rejection of organ transplant
cross-presentation
exogenous antigen presented by MHC-I
DC is licensed by CD4+ T cell
exogenous antigen is redirected into endogenous pathway
DC present antigen with MHC-I
activation of CD8+ T cell
MHC genetics
HLA genes
MHC-I genes
HLA-
A
HLA-
B
HLA-
C
MHC-II genes
HLA-
D..
polymorphism
variations exist in a gene
Ex. HLA-A1 vs HLA-A2 (HLA-A genes)
differences clustered at groove
haplotype
of parents are inherited
heterozygous
at each allele
MHC alleles are
codominantly expressed
polygeny
multiple genes with same function
,
slightly different structure
Ex. HLA-A vs HLA-B
co-receptors
of T cell
types
CD8
30-40% of T cells
cytotoxic T cell
recognize
pMHC-I
heterodimer
š¶ chain + š· chain (TMs)
Ig-like domain in š¶, š· chain
CD4
60-70% of T cells
helper T cell
single TM domain
4 Ig-like domain
recognize
pMHC-II
functions
enhance TCR-pMHC interaction
initiate
signal 1
(
activation signal
)
signaling
adaptor & binding domain
molecular interactions are determined by domains
formation of multimolecular complexes
phosphorylation
ubiquitination
receptor
intrinsic
kinase activity
no intrinsic
kinase activity
recruit kinase
signal 1 activation
pMHC--TCR
co-receptor
associated
kinase
activates
ITAM domains on TCR and CD3
ITAMs recruit
Zap-70
Zap-70 (kinase)
activates four signaling molecule
many signaling cascades are initiated
transcription
of many genes
activation of T cell
signal 2 survival
costimulatory ligands
ligands on APC:
B7.1
and
B7.2
receptor on T cell:
CD28
phosphorylation of CD28
recruit other kinases for additional signaling
clonal anergy
missing costimulatory signal
anergic T cell no longer
respond to stimulation
signal 3 differentiation
cytokines (IL-2)
autocrine fashion
transcription of
IL-2 & IL-2R š¶
activated by
signal 1& 2
IL-2 R š·šø are constitutively expressed
IL-2 R š¶ enhance the affinity towards IL-2
proliferation
of effector
clonal cell population
and memory