lecture 8 Immune receptors and signal Transduction Flashcards
1
Q
what do adaptor proteins lack
A
catalytic activity
2
Q
what do adaptor proteins have
A
protein-protein interaction domains
3
Q
what exactly are adaptor proteins
A
molecular hubs that link enzymes and assembly signaling molecule complexes
4
Q
examples of adaptor proteins
A
LAT, BLNK
5
Q
LAT
A
linker for activation of T cells
6
Q
BLNK
A
B cell linker
7
Q
what types of domains do adaptor proteins have
A
SH2 and SH3
8
Q
how are adaptor proteins connected to proteins w/ SH2 domains
A
have tyrosine residues for docking sites due to phosphotyrosine
9
Q
what does adaptor protein have for connection w/ SH3 domains on other proteins
A
proline-rich stretches
10
Q
what is central for T cell signaling
A
LAT
11
Q
how was LAT signifigance demonstrated
A
Jurkat T cells lacked LAT and no TCR mediated signaling but if restore then had signaling and T cell activation
12
Q
what are Jurkat T cells
A
tumor cells
13
Q
if animals lack LAT how are they different
A
no mature alpha or beta T cells
14
Q
what happens in T cell activation
A
assembly proper adaptor proteins
15
Q
main adaptor proteins to activate T cells
A
LAT, GADS/Grb2, SLP 76
16
Q
what type of protein is LAT
A
integral membrane protein
17
Q
What is the role of LAT in T cell activation
A
is phosphorylated and recruits PLCy and GADs
18
Q
what does PLCy do
A
Ca2+ signaling
19
Q
what is fxn of GADS
A
associates w/ SLP76 by SH3 domains
20
Q
GADS is what type of protein and family
A
cytosolic adaptor protein of Grb2 family
21
Q
what is SLP16 for
A
recruits VAV
22
Q
activates SLP76
A
TK
23
Q
what type of protein is SLP 76
A
adaptor protein w/ proline rich domain and SH2 binding domain
24
Q
what is role of VAV
A
activate cytoskeletal rearrangements and Tc alterations
25
what type of proteins are VAV
guanine nucleotide exchanges factors for GTPases
26
what makes up the TCR complex
a/B TCR non-covalently liked to CD3 and weird G protein
27
list order of TCR complex
CD3, G, TCR, CD3
28
what causes the parts of TCR complex to join
charged residues in transmembrane region
29
size of a and B carboxyl terminal cytoplasmic tails
5-12 aa long
30
what is the role of CD3 and weird G in TCR complex
signal- transducing subunit due to the small TCR cytoplasmic tails
31
chains of CD3 are
epsilon and delta
32
what do CD8 and CD4 react with
MHC class I and II
33
describe CD4 coreceptors
4 extracellular Ig-linke domains, hydrophobic transmembrane, basic cytoplasmic tail of 38 AA
34
what are CD4 coreceptor ig like domains
2 variable and 2 H that alternate
35
what makes up CD8 coreceptor
CD8 alpha and beta
36
structure of CD8 alpha and beta coreceptor
single IG domain, transmembrane, basic cytoplasmic tail of 25 aa long
37
CD8 coreceptors bind what
MHC class I and Beta 2 microglobulin
38
activating receptors of immune system
ITAMS
39
what is the structure of ITAMs
separate polypeptide chains for recognition and signaling such as TCR
40
what does ITAM stand for
immunoreceptor tyrosine-based activating motifs
41
where are itams on activating receptors
cytosolic
42
inhibitory receptors have what
ITIMs on cytosolic
43
structure of inhibitory receptor
recognition and signaling domain on same side
44
inhibitory receptor in B cells and myeloid cells
FcyRIIB
45
Fc receptor for IgE
FcERI
46
Fc receptor for IgG
FcyRIIB
47
how many signaling chains does a TCR complex have
6: 2 CD3, 2 weird G, 2 CD3
48
how many ITAMS does a TCR complex have
10: 2 CD3, 6 weird G, 2 CD3
49
how is Ag affinity for TCR determined
number of ITAMS phosphorylated
50
stronger, longer Ag to TCR means
more ITAMs phosphorylated
51
what does Ag affinity of TCR determine
nature/stage of cellular response
52
weak TCR to Ag signal means
positive selection of T cells in thymus
53
strong TCR to Ag signal means
negative selection of T cells and death by apoptosis
54
what regulates TCR and BCR besides ITAMs and ITIMs
coreceptors, costimulation, and inhibitory receptors
55
what is a co-receptor
transmembrane signaling protein on lymphocyte that stimulates AG receptor activation
56
what does a coreceptor with signaling enzyme cause for normal receptor
increase ITAM phosphorylation and activation of Ag receptor
57
Co receptor on T helper cells
CD4
58
co receptor on cytotoxic T cells
CD8
59
co receptor on B cells
CR2/ CD21
60
costimulate activation of T cells
CD28- CD80/86
61
inhibitor of TCR activation
CTLA 4 as analog of CD28
62
inhibitory receptors in B cells
CD22 and FcyRIIB
63
what is the first signal for TCR activation
recognition of MHC- peptide complex
64
what is the second signal for T cell activation
CD28 bound to CD80 or 86.
65
what causes T cell inhibition
expression of CTLA-4
66
why does CTLA-4 work so well for inhibiton of T cells
has higher affinity to CD 80/86 compared to CD28
67
what does T cell inhibition cause
down regulates T cell function and inhibits expansion of activated T cells
68
what happens on ag recognition BY TCR
complexes cluster with CD4 or CD8
69
what determines CD4 or CD8 clustering w/ TCR complexes
CD4 is on helper T cells that bind MHC class II on APC while CD8 on cytotoxic T cells bind MHC class I
70
what happens after TCR clusters w/ CD4/8
activates and phosphorylates ITAMS of CD3 and weird G chains
71
what is associated w/ CD4
Lck that goes into the cell and phosphorylates that ITAMS
72
how does zap 70 come into play with T cell activation
binds phosphotyrosines on weird G chains
73
what part of early T cell activation if self-phosphorylated and activated
ZAP70 to weird G chains
74
what is activated by ZAP-70 in T cell activation
adaptor proteins by phosphorylation
75
what are the adaptor proteins used for in T cell activation
docking site for phospholipase C gamma 1 and exchange factors
76
what do exchange factors do in T cell activation
activate RAS and MAP kinases
77
what do TCR do when not active
have basal levels of ITAM phosphorylation and some recruitment of ZAP 70 binding these
78
what does PLCy1 bind before activation
LAT
79
what activates PLCy
ZAP 70
80
if ZAP 70 binds to phosphotyrosines, what domain do they have
SH2
81
what does activated PLCy1 do
hydrolyzes PIP2 and makes IP3 and DAG
82
where is PIP2 located
membrane
83
what is IP3
inositol triphosphate
84
what does IP3 do
stimulates increase in cytosolic Ca2+ released from ER
85
DAG
diacyl-glycerol
86
what is the role of DAG
activates protein Kinase C
87
what is the result of PKC and Ca2+ activation
many cellular responses
88
What is transactivated with Ag- stimulated T cells
IL2
89
PKC can activate
NF-kB
90
what is NF-kB
p50p60 homeodimer
91
what is the state of NF-kB before activation
inactivated by IkB
92
how does PKC activate NF-kB
phosphorylates IkB to dissociate from NF-kB
93
where does NF-kB go once activated
nucleus
94
similar molecule to NF-kB that is activated by Ca2+
NFAT
95
how is NFAT activated by Ca2+
Ca2+ bind calmodulin that dephosphorylates NFAT for activation
96
where can NFkB be activated
T and B lymphocytes as well as other immune cells
97
what can lead to activation of canonical pathway if NFkB
series of stimuli
98
NFkB with IKK
activated IKK phosphorylates IkB on 2 serine residues
99
what is induced with IkB proteins
IkB polyubiquinylation
100
why does IkB need to be ubiquinated
leads to digestion by proteasome so NFkB dimer can be moved into nucleus for Tc
101
what makes up NFkB
p65/cRef and p50
102
what are the two thinks specifically activated by LAT
helps to activate PLCy and Binds Grb2
103
What happens after GADS/ Grb-2 is bound by LAT
GTP/GDP exchange factor SOS docks
104
what is the role of SOS
convert RAS GDP to RAS GTP
105
what is the role of RAS-GTP
activate MAP kinase and ERK
106
what is the total effect of RAS-MAP kinase activation
AP-1 activation and other TFs
107
SOS means
son of sevenless, set of genes encoding guanine nucleotide exchange factors
108
RAS
Ras sarcoma is a subset of small GTPases
109
what activates all MAP kinases
phosphorylation
110
3 major groups of map kinases
ERK, p38 MAP kinase, JNK
111
what does ERK activate
ELK-P
112
what is ELK-P
TF that activates TC of TF FOS
113
What does RAC-GTP do
activates p38 and JNK
114
what does JNK do
phosphorylates Jun
115
role of Jun-P in T cells
goes from cytoplasm into nucleus where it joins with FOS
116
name of Jun-P and FOS together
AP-1 early response transcription factor
117
What does AP1 activation lead to
IL2 mRNA
118
what are two pathways that activate MAP kinases in T cells
Ras-GDP and Rac-GTP
119
what is required for TH activation
Cd 80/86 as well as
120
what happens if MHC II bind to CD4 cells without CD 80/86
activate cell death or anergy
121
what is anergy
T cell unresponsiveness, clonal anergy
122
what type of state is clonal anergy
hyporesponsive state
123
what does hyporesponsive mean
reduced ability to make IL2
124
what can stop anergy
exogenous IL2
125
what can cause anergy
increased levels of Ag without CD 28 to CD 80/86 coreceptors on T cells and APCs
126
what can also be a costimulatory signal for T cells that the loss of would induce anergy
cytokine signaling such as IL2
127
signal one of T cell activation
TCR with MHC
128
what is signal 2 of T cell activation
CD 28 with CD 80/86
129
how do CD 28 and TCR work together
induce different pathways that lead to activation when both are present but anergy when CD 28 is absent
130
what do TCR activate without CD 28 specificaly
Calcium/ calmodulin activation of NFAT only
131
NFAT alone causes
gene expression of anergy inducing genes
132
what does the presence of CD 28 do to change NFAT
NF-kB and AP1 work with NFAT to cause gene expression of productive genes
133
what pathways lead to NF-kB and AP1 production
PKC, RAS-MAPK, IKK
134
what is the overall goal of T cell activation
IL2 production
135
what are the major products for CD4+ activation
TCR to MHC class II, CD28-80/86, CD4 itself to MHC II, LFA-1 with ICAM
136
what is LFA-1 and ICAM for
adhesion to help reaction of T cell activation
137
Receptors for CD8 activation
TCR to MHC I, CD 8 to MHC class I, CD 28-80/86, LFA-1 to ICAM-1
138
ITAMS in T cell activation do what
they are signaling proteins that phosphorylate and dock signaling molecules
139
what makes up CD3 of TCR complex
3 polypeptide chains : gamma, sigma and epsilon
140
how does pairing work for CD3 on TCR complex
gamma with epsilon and sigma with epsilon
141
homolog of CD 28
CTLA 4, cytotoxic T lymphocyte antigen 4, causes negative regulation of TCR activation
142
what is PD-1
program death -1 that causes negative regulation of signal production
143
where is the only place to find CD4
APCs so with extracellular antigens and T helper cells.
144
APCs include
dendritic, phagocytes, B cells, endothelial cells and Thymic epithelium
145
how was the synapse of APC to t cells modeled
Talin binds with LFA-1 and is labeled green for antibodies
146
PKC-delta does what
goes with TCR complex for Texas red labeled Abs
147
what is at the center of T cell synapse
TCR with PKC delta and surrounded by Talin with LFA-1
148
how many LFA-1 and ICAM -1 bindings occur in TCR
10
