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immunology > lecture 8 Immune receptors and signal Transduction > Flashcards

lecture 8 Immune receptors and signal Transduction Flashcards

1
Q

what do adaptor proteins lack

A

catalytic activity

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2
Q

what do adaptor proteins have

A

protein-protein interaction domains

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3
Q

what exactly are adaptor proteins

A

molecular hubs that link enzymes and assembly signaling molecule complexes

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4
Q

examples of adaptor proteins

A

LAT, BLNK

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5
Q

LAT

A

linker for activation of T cells

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6
Q

BLNK

A

B cell linker

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7
Q

what types of domains do adaptor proteins have

A

SH2 and SH3

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8
Q

how are adaptor proteins connected to proteins w/ SH2 domains

A

have tyrosine residues for docking sites due to phosphotyrosine

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9
Q

what does adaptor protein have for connection w/ SH3 domains on other proteins

A

proline-rich stretches

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10
Q

what is central for T cell signaling

A

LAT

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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

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12
Q

what are Jurkat T cells

A

tumor cells

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13
Q

if animals lack LAT how are they different

A

no mature alpha or beta T cells

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14
Q

what happens in T cell activation

A

assembly proper adaptor proteins

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15
Q

main adaptor proteins to activate T cells

A

LAT, GADS/Grb2, SLP 76

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16
Q

what type of protein is LAT

A

integral membrane protein

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17
Q

What is the role of LAT in T cell activation

A

is phosphorylated and recruits PLCy and GADs

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18
Q

what does PLCy do

A

Ca2+ signaling

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19
Q

what is fxn of GADS

A

associates w/ SLP76 by SH3 domains

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20
Q

GADS is what type of protein and family

A

cytosolic adaptor protein of Grb2 family

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21
Q

what is SLP16 for

A

recruits VAV

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22
Q

activates SLP76

A

TK

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23
Q

what type of protein is SLP 76

A

adaptor protein w/ proline rich domain and SH2 binding domain

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24
Q

what is role of VAV

A

activate cytoskeletal rearrangements and Tc alterations

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25
Q

what type of proteins are VAV

A

guanine nucleotide exchanges factors for GTPases

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26
Q

what makes up the TCR complex

A

a/B TCR non-covalently liked to CD3 and weird G protein

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27
Q

list order of TCR complex

A

CD3, G, TCR, CD3

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28
Q

what causes the parts of TCR complex to join

A

charged residues in transmembrane region

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29
Q

size of a and B carboxyl terminal cytoplasmic tails

A

5-12 aa long

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30
Q

what is the role of CD3 and weird G in TCR complex

A

signal- transducing subunit due to the small TCR cytoplasmic tails

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31
Q

chains of CD3 are

A

epsilon and delta

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32
Q

what do CD8 and CD4 react with

A

MHC class I and II

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33
Q

describe CD4 coreceptors

A

4 extracellular Ig-linke domains, hydrophobic transmembrane, basic cytoplasmic tail of 38 AA

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34
Q

what are CD4 coreceptor ig like domains

A

2 variable and 2 H that alternate

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35
Q

what makes up CD8 coreceptor

A

CD8 alpha and beta

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36
Q

structure of CD8 alpha and beta coreceptor

A

single IG domain, transmembrane, basic cytoplasmic tail of 25 aa long

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37
Q

CD8 coreceptors bind what

A

MHC class I and Beta 2 microglobulin

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38
Q

activating receptors of immune system

A

ITAMS

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39
Q

what is the structure of ITAMs

A

separate polypeptide chains for recognition and signaling such as TCR

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40
Q

what does ITAM stand for

A

immunoreceptor tyrosine-based activating motifs

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41
Q

where are itams on activating receptors

A

cytosolic

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42
Q

inhibitory receptors have what

A

ITIMs on cytosolic

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43
Q

structure of inhibitory receptor

A

recognition and signaling domain on same side

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44
Q

inhibitory receptor in B cells and myeloid cells

A

FcyRIIB

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45
Q

Fc receptor for IgE

A

FcERI

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46
Q

Fc receptor for IgG

A

FcyRIIB

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47
Q

how many signaling chains does a TCR complex have

A

6: 2 CD3, 2 weird G, 2 CD3

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48
Q

how many ITAMS does a TCR complex have

A

10: 2 CD3, 6 weird G, 2 CD3

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49
Q

how is Ag affinity for TCR determined

A

number of ITAMS phosphorylated

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50
Q

stronger, longer Ag to TCR means

A

more ITAMs phosphorylated

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51
Q

what does Ag affinity of TCR determine

A

nature/stage of cellular response

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52
Q

weak TCR to Ag signal means

A

positive selection of T cells in thymus

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53
Q

strong TCR to Ag signal means

A

negative selection of T cells and death by apoptosis

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54
Q

what regulates TCR and BCR besides ITAMs and ITIMs

A

coreceptors, costimulation, and inhibitory receptors

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55
Q

what is a co-receptor

A

transmembrane signaling protein on lymphocyte that stimulates AG receptor activation

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56
Q

what does a coreceptor with signaling enzyme cause for normal receptor

A

increase ITAM phosphorylation and activation of Ag receptor

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57
Q

Co receptor on T helper cells

A

CD4

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58
Q

co receptor on cytotoxic T cells

A

CD8

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59
Q

co receptor on B cells

A

CR2/ CD21

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60
Q

costimulate activation of T cells

A

CD28- CD80/86

61
Q

inhibitor of TCR activation

A

CTLA 4 as analog of CD28

62
Q

inhibitory receptors in B cells

A

CD22 and FcyRIIB

63
Q

what is the first signal for TCR activation

A

recognition of MHC- peptide complex

64
Q

what is the second signal for T cell activation

A

CD28 bound to CD80 or 86.

65
Q

what causes T cell inhibition

A

expression of CTLA-4

66
Q

why does CTLA-4 work so well for inhibiton of T cells

A

has higher affinity to CD 80/86 compared to CD28

67
Q

what does T cell inhibition cause

A

down regulates T cell function and inhibits expansion of activated T cells

68
Q

what happens on ag recognition BY TCR

A

complexes cluster with CD4 or CD8

69
Q

what determines CD4 or CD8 clustering w/ TCR complexes

A

CD4 is on helper T cells that bind MHC class II on APC while CD8 on cytotoxic T cells bind MHC class I

70
Q

what happens after TCR clusters w/ CD4/8

A

activates and phosphorylates ITAMS of CD3 and weird G chains

71
Q

what is associated w/ CD4

A

Lck that goes into the cell and phosphorylates that ITAMS

72
Q

how does zap 70 come into play with T cell activation

A

binds phosphotyrosines on weird G chains

73
Q

what part of early T cell activation if self-phosphorylated and activated

A

ZAP70 to weird G chains

74
Q

what is activated by ZAP-70 in T cell activation

A

adaptor proteins by phosphorylation

75
Q

what are the adaptor proteins used for in T cell activation

A

docking site for phospholipase C gamma 1 and exchange factors

76
Q

what do exchange factors do in T cell activation

A

activate RAS and MAP kinases

77
Q

what do TCR do when not active

A

have basal levels of ITAM phosphorylation and some recruitment of ZAP 70 binding these

78
Q

what does PLCy1 bind before activation

A

LAT

79
Q

what activates PLCy

A

ZAP 70

80
Q

if ZAP 70 binds to phosphotyrosines, what domain do they have

A

SH2

81
Q

what does activated PLCy1 do

A

hydrolyzes PIP2 and makes IP3 and DAG

82
Q

where is PIP2 located

A

membrane

83
Q

what is IP3

A

inositol triphosphate

84
Q

what does IP3 do

A

stimulates increase in cytosolic Ca2+ released from ER

85
Q

DAG

A

diacyl-glycerol

86
Q

what is the role of DAG

A

activates protein Kinase C

87
Q

what is the result of PKC and Ca2+ activation

A

many cellular responses

88
Q

What is transactivated with Ag- stimulated T cells

A

IL2

89
Q

PKC can activate

A

NF-kB

90
Q

what is NF-kB

A

p50p60 homeodimer

91
Q

what is the state of NF-kB before activation

A

inactivated by IkB

92
Q

how does PKC activate NF-kB

A

phosphorylates IkB to dissociate from NF-kB

93
Q

where does NF-kB go once activated

A

nucleus

94
Q

similar molecule to NF-kB that is activated by Ca2+

A

NFAT

95
Q

how is NFAT activated by Ca2+

A

Ca2+ bind calmodulin that dephosphorylates NFAT for activation

96
Q

where can NFkB be activated

A

T and B lymphocytes as well as other immune cells

97
Q

what can lead to activation of canonical pathway if NFkB

A

series of stimuli

98
Q

NFkB with IKK

A

activated IKK phosphorylates IkB on 2 serine residues

99
Q

what is induced with IkB proteins

A

IkB polyubiquinylation

100
Q

why does IkB need to be ubiquinated

A

leads to digestion by proteasome so NFkB dimer can be moved into nucleus for Tc

101
Q

what makes up NFkB

A

p65/cRef and p50

102
Q

what are the two thinks specifically activated by LAT

A

helps to activate PLCy and Binds Grb2

103
Q

What happens after GADS/ Grb-2 is bound by LAT

A

GTP/GDP exchange factor SOS docks

104
Q

what is the role of SOS

A

convert RAS GDP to RAS GTP

105
Q

what is the role of RAS-GTP

A

activate MAP kinase and ERK

106
Q

what is the total effect of RAS-MAP kinase activation

A

AP-1 activation and other TFs

107
Q

SOS means

A

son of sevenless, set of genes encoding guanine nucleotide exchange factors

108
Q

RAS

A

Ras sarcoma is a subset of small GTPases

109
Q

what activates all MAP kinases

A

phosphorylation

110
Q

3 major groups of map kinases

A

ERK, p38 MAP kinase, JNK

111
Q

what does ERK activate

A

ELK-P

112
Q

what is ELK-P

A

TF that activates TC of TF FOS

113
Q

What does RAC-GTP do

A

activates p38 and JNK

114
Q

what does JNK do

A

phosphorylates Jun

115
Q

role of Jun-P in T cells

A

goes from cytoplasm into nucleus where it joins with FOS

116
Q

name of Jun-P and FOS together

A

AP-1 early response transcription factor

117
Q

What does AP1 activation lead to

A

IL2 mRNA

118
Q

what are two pathways that activate MAP kinases in T cells

A

Ras-GDP and Rac-GTP

119
Q

what is required for TH activation

A

Cd 80/86 as well as

120
Q

what happens if MHC II bind to CD4 cells without CD 80/86

A

activate cell death or anergy

121
Q

what is anergy

A

T cell unresponsiveness, clonal anergy

122
Q

what type of state is clonal anergy

A

hyporesponsive state

123
Q

what does hyporesponsive mean

A

reduced ability to make IL2

124
Q

what can stop anergy

A

exogenous IL2

125
Q

what can cause anergy

A

increased levels of Ag without CD 28 to CD 80/86 coreceptors on T cells and APCs

126
Q

what can also be a costimulatory signal for T cells that the loss of would induce anergy

A

cytokine signaling such as IL2

127
Q

signal one of T cell activation

A

TCR with MHC

128
Q

what is signal 2 of T cell activation

A

CD 28 with CD 80/86

129
Q

how do CD 28 and TCR work together

A

induce different pathways that lead to activation when both are present but anergy when CD 28 is absent

130
Q

what do TCR activate without CD 28 specificaly

A

Calcium/ calmodulin activation of NFAT only

131
Q

NFAT alone causes

A

gene expression of anergy inducing genes

132
Q

what does the presence of CD 28 do to change NFAT

A

NF-kB and AP1 work with NFAT to cause gene expression of productive genes

133
Q

what pathways lead to NF-kB and AP1 production

A

PKC, RAS-MAPK, IKK

134
Q

what is the overall goal of T cell activation

A

IL2 production

135
Q

what are the major products for CD4+ activation

A

TCR to MHC class II, CD28-80/86, CD4 itself to MHC II, LFA-1 with ICAM

136
Q

what is LFA-1 and ICAM for

A

adhesion to help reaction of T cell activation

137
Q

Receptors for CD8 activation

A

TCR to MHC I, CD 8 to MHC class I, CD 28-80/86, LFA-1 to ICAM-1

138
Q

ITAMS in T cell activation do what

A

they are signaling proteins that phosphorylate and dock signaling molecules

139
Q

what makes up CD3 of TCR complex

A

3 polypeptide chains : gamma, sigma and epsilon

140
Q

how does pairing work for CD3 on TCR complex

A

gamma with epsilon and sigma with epsilon

141
Q

homolog of CD 28

A

CTLA 4, cytotoxic T lymphocyte antigen 4, causes negative regulation of TCR activation

142
Q

what is PD-1

A

program death -1 that causes negative regulation of signal production

143
Q

where is the only place to find CD4

A

APCs so with extracellular antigens and T helper cells.

144
Q

APCs include

A

dendritic, phagocytes, B cells, endothelial cells and Thymic epithelium

145
Q

how was the synapse of APC to t cells modeled

A

Talin binds with LFA-1 and is labeled green for antibodies

146
Q

PKC-delta does what

A

goes with TCR complex for Texas red labeled Abs

147
Q

what is at the center of T cell synapse

A

TCR with PKC delta and surrounded by Talin with LFA-1

148
Q

how many LFA-1 and ICAM -1 bindings occur in TCR

A

10

immunology (10 decks)

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