Mechanisms of Cellular
Communication: Signaling in the Immune
System
Vet Sci 432(3 credits)
I.
Introduction
to signaling.
A.
General
Principles of Signaling
1.
tyrosine
phosphorylation
a.
PTKs
b.
PTPases
2.
receptor
dimerization
3.
recruitment
of downstream signaling molecules
B.
Protein/protein
interactions
1.
Protein
modules (SH2,SH3, PH, PTB)
2.
Adaptor
proteins
3.
Docking/Scaffolding
proteins
C.
Signaling
networks
1.
control
of MAP Kinase signaling
2.
PI3K/Akt
and cell survival
3.
GTP-binding
proteins
II.
Immunoglobulin
receptors.
A.
BCR/TCR/
Fc receptors
1.
receptor
structure
2.
co-receptors
3.
associated
protein tyrosine kinases
B.
Downstream
effectors
1.
NFAT
2.
AP1
C.
Negative
feedback regulation
1. role of
SHIP
III.
Cytokine
Receptors (interferons and interleukins)
A.
Structure
1. common
subunits
B.
Jak/Stat
pathways
1.
specificity/redundancy-
lessons from knockouts
C.
Negative
regulation
a.
phosphatases
b.
SOCS
– a new family of cytokine-inducible signaling inhibitors
D.
Interferon-g receptor signaling
1.
IRF
family of transcriptional regulators
2. Role in Th differentiation and macrophage activation
E.
IL-1b
1.
conservation
through evolution (Toll)
2.
IL-1b converting enzyme
IV.
TNF
Receptor Family
A.
Structure
1.
“Death
domains”
B.
Components
of signaling cascade
1.
Activation of NF-kB
2.
TRAFs, TRADDs and FADDs and apoptosis
C.
TNF-a
1.
Role
in macrophage activation/ inflammation
D.
Fas
1.
removal
of activated lymphocytes
2.
Autoimmunity
(lpr/gld mice)
V.
Integrins
A.
Classification of integrins (a and b subunits)
B.
“Inside-out”
signaling
C.
Role
of focal adhesion kinases
D.
Src
protein kinases
E.
Convergence
and synergy with RTK signaling pathways
F.
Roles
in leukocyte function
1.
VLA-4
in T cell activation
2.
a6b4 in chemotaxis and phagocytosis
VI.
Chemokine
Receptors
A.
CXC
vs. CC chemokine receptors
1.
Signaling
mechanisms?
2.
Chemokines,
leukocyte trafficking and inflammation
B.
IL-8,
GCP-2 and neutrophil chemotaxis
C. SDF-1 and
hematopoiesis
VII.
Signaling
pathways and immunity to infection – putting it all together
A.
Intracellular
Bacteria
1.
Listeria monocytogenes as a probe to study
cell-mediated immunity
2.
Susceptibility
to mycobacterial infection in man
B.
Parasites
1.
Protective immunity against Leishmania major
C.
Viral
immunity
1. IFN-a/b and viral immunity
2.
Chemokines
and HIV