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Immunology Test II > Immune Receptors and Signal Transduction > Flashcards

Immune Receptors and Signal Transduction Flashcards

1
Q

TCR signaling deficiency can be cause by what?

A 
Deficiencies in :
CD40 ligand
CD40 
CD3γ
CD8
ZAP - 70
Ca ++ channel 
CD25
STAT5b
Itk
DOCK8
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2
Q

Generally, receptors are what kind of protein?

A

Integral membrane proteins present on the plasma membrane

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3
Q

What do extracellular domains of receptors recognize?

A

Soluble ligands or membrane structures of neighboring cells

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4
Q

What are nuclear receptors?

A

Intracellular transcription factors that are activated by lipid-soluble ligands that can cross the plasma membrane

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5
Q

What does ligand-binding involve?

A

A conformational alteration of the receptor

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6
Q

What does signaling require?

A

A ligand-induced clustering of receptors

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7
Q

What is cross-linking?

A

Clustering of receptors that is ligand-induced

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8
Q

What does clustering and conformational alterations result in?

A

Changes in the cytosolic portion of the receptor that promotes interactions with other signaling molecules

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9
Q

What initiates the signal transduction?

A

The enzymatic phosphorylation of tyrosine, serine, or threonine in the cytosolic portion

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10
Q

The enzymes that phosphorylate tyrosine, serine, threonine, or lipid substrates are called what?

A

Protein kinases:
Tyrosine kinases
Serine/threonine kinases
Lipid kinases

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11
Q

What removes the phosphate residue and thus modulate signaling?

A

Specific phosphatases for all types of protein kinases

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12
Q

(Kinases/phosphatases) usually play inhibitory roles in signal transduction

A

Phosphatases

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13
Q

What either targets proteins for degradation or drive signal transduction in many cells?

A

The covalent addition of ubiquitin molecules

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14
Q

What may promote plasma membrane localization signaling molecules?

A

Protein signaling molecules modified by the addition of lipids

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15
Q

What modulates gene expression, DNA replication, and DNA recombination events?

A

Acetylation and methylation of the N-terminal tails of histones

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16
Q

What are the major categories of receptors?

A 
Non-receptor tyrosine kinase
Receptor tyrosine kinases
Nuclear receptors
G protein-coupled receptors
Notch
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17
Q

What are the tyrosine kinase families?

A

The Src family, Syk family, and the Tec family

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18
Q

What are tyrosine kinases of the Src family?

A

c-Src, Lyn, Fyn, and Lck

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19
Q

What are tyrosine kinases of the Syk family?

A

Syk and ZAP-70

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20
Q

What are tyrosine kinases of the Tec family?

A

Tec, Btk, and Itk

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21
Q

What are signaling molecules composed of?

A

Distinct modules, each with a specific binding or catalytic function

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22
Q

What are the unique domains of tyrosine kinases?

A

SH2 domain
SH3 domain
PH domain

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23
Q

What is the function of the SH2 domain?

A

Bind to specific phosphotyrosine-containing polypeptides of certain proteins

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24
Q

What is the function of SH3 domains?

A

Recognize and bind to proline-rich stretches in certain polypeptides

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25
Q

What is the function of PH domains?

A

Recognize PIP3 or other phosphatidylinositol-derived lipids

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26
Q

What are SH2 domains composed of?

A

100 amino acids folded into a particular formation

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27
Q

What serves as binding sites for SH2 domains present in Syk and ZAP-70 tyrosine kinases?

A

The phosphotyrosine motifs in the Ag receptor complex

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28
Q

What are SH3 domains composed of?

A

100 amino acids in length

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29
Q

What do pleckstrin homology (PH) domains recognize?

A

recognize specific phospholipids

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30
Q

What does the TEC family tyrosine kinase Btk recongize?

A

Recognize phophatidylinositol trisphosphate (PIP3)

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31
Q

What is PIP3?

A

A lipid moiety on the inner leaflet of the plasma membrane

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32
Q

What are adaptor proteins?

A

Molecular hubs that physically link different enzymes and promote the assembly of complexes of signaling molecules

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33
Q

What are examples of adaptor proteins?

A

LAT and BLNK

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34
Q

What is the linker for the activation of T cells?

A

LAT

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35
Q

What is the B cell linker (Adaptor)?

A

BLNK

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36
Q

What may adaptor proteins contain a few of?

A

Few SH2 and SH3 domains

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37
Q

What do adaptor proteins often contain?

A

Often contain some proline-rich stretches that can bind other proteins that contain SH3 domains

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38
Q

Adaptor proteins contain tyrosine residues that may be phosphorylated by tyrosine kinases and serve as what?

A

Docking sites for other signaling molecules with SH2 domains

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39
Q

What is an integral membrane protein that functions as an adaptor in T cell activation?

A

LAT

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40
Q

What are two cytosolic adaptors involved in T cell activation?

A

GADS and SLP-76

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41
Q

Upon T cell activation what cascades happen with the adaptors of the T cell?

A

Lat is phosphorylated and recruits PLCγ (phosphoinositide phospholipase c) and the GADS adaptor (both contain SH2 domains)
Proline-rich amino acid stretch in SLP-76 associates with an SH3 domain of GADS - this then recruits Vav after being trysoine-phosphorylated

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42
Q

What are the four examples of the immune receptor family?

A

The B cell receptor (BCR)
T cell receptor (TCR)
High-affinity receptor for IgE (FceRI)
And inhibitory receptor found on B cells and myeloid cells (FCγRIIB)

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43
Q

What do activating immune receptors have?

A

Separate polypeptide chains for recognition and associated signaling polypeptide chains that contain cytosolic ITAMs

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44
Q

What does ITAMs stand for?

A

Immunoreceptor tyrosine-based activating motifs

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45
Q

What to inhibitory receptors in the immune system typically have?

A

They have ITIMs on the cytosolic portion of the same chain that uses its extracellular domain for ligand recognition

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46
Q

What inhibitory receptor is found on B cells and myeloid cells?

A

FcγRIIB

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47
Q

TCR and BCR signaling is (similar/different)

A

Similar

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48
Q

What does Ag binding and clustering results in?

A

Activation of an associated Src family kinase

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49
Q

What may expose tyrosine residues of a ITAM motif?

A

Conformational change or unfolding of the cytoplasmic tail of the receptor

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50
Q

What do Src family kinase phosphorylate?

A

Available tyrosines in the ITAMs

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51
Q

What are recognized by a Syk family tyrosine kinase that has tandem SHA2 domains

A

Two phosphorylated tyrosines in a single ITAM

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52
Q

What does each SHD domain of Syk family tyrosine kinase bind to?

A

An ITAM phosphotyrosine

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53
Q

What does recruited and activated Syk family kinase phosphorylate?

A

Adaptor proteins and enzymes that activate distinct signaling pathways downstream of the immune receptor

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54
Q

How many signaling chains and ITAMS does the TCR complex have?

A

6x signaling chains and 10x ITAMS

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55
Q

What does stronger or prolonged binding of Ag to the TCR results in?

A

Increasing numbers of phosphorylated ITAMs

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56
Q

What is the cytosolic interpretation of Ag affinity to the TCR?

A

The number of ITAMs phosphorylated

57
Q

What can influence the nature of the cellular response at different stages of differentiation and activation?

A

Ag affinity of TCR

58
Q

What are required for positive selection of T cells in the thymus?

A

Weak TCR signals

59
Q

What results in thymocyte death by apoptosis?

A

Strong TCR signals in the thymus

60
Q

What is a corereceptor?

A

A transmembrane signaling protein on a lymphocyte that can facilitate Ag receptor activation

61
Q

What are the three mechanisms that fine-tune and modulate antigen receptor signaling?

A

Progressive ITAM use
Increased cellular activation by coreceptors
Modulation of signaling by inhibitory receptors

62
Q

The coreceptor with its signaling enzymes can do what?

A

Increase ITAM phosphorylation and activation of the antigen receptor

63
Q

What are coreceptors on T helper and cytotoxic T cells, respectively?

A

CD4 and CD8 proteins

64
Q

What is the coreceptor on B cells?

A

Complement receptor type 2 (CR2/CD21)

65
Q

What is the inhibitory T cell receptor?

A

CTLA-4

66
Q

What are the inhibitory receptors in B cells?

A

CD22 and FCγRIIB

67
Q

What are the costimulatory molecules and prototypic costimulatory receptors on T cells?

A

CD28 (receptor)

CD80/86 (costimulatory molecules)

68
Q

What do costimulatory receptors add?

A

Add another level of control to the process of lymphocyte activation

69
Q

What do costimulatory receptors provide?

A

So-called second signals for lymphocytes and ensure that immune responses are optimally triggered by infectious pathogens and substances that mimic microbes

70
Q

Cognate peptide recognition in the presence of co-stimulation results in:

A

Th-cell activation

71
Q

Cognate peptide recognition in the absence of co-stimulation results in:

A

Activation-induced cell death or anergy

72
Q

What are the components of TCR?

A

α and β chains

73
Q

What are the componets of Ig?

A

heavy and light chains

74
Q

What is the number of Ig domains in TCR?

A

One V domain and one C domain in each chain

75
Q

What is the number of Ig domains in Igs?

A

Heavy chain: one V domain, three or four C domains

Light chain: One V domain and one C domain

76
Q

What is the number of CDRs involved in Ag binding in TCR?

A

Six (three in each chain)

77
Q

What is the number of CDRs involved in Ag binding in Ig?

A

Six (three in each chain)

78
Q

What are the associated signaling molecules of TCR?

A

CD3 an ζ

79
Q

What are the associated signaling molecules of Ig?

A

Igα and Igβ

80
Q

What is the affinity for Ag (Kd) with TCR?

A

10^-5 - 10^-7 M

81
Q

What is the affinity for Ag (Kd) with Ig?

A

10^-7 - 10^-11 M (secreted Ig)

82
Q

What does the TCR complex consist of?

A

The αβ TCR non-covalently linked to the CD3 and ζ proteins

83
Q

The association of proteins, of the TCR complex, with one another is mediated by what?

A

Their charged residues in their transmembrane regions

84
Q

What do both of the TCR chains, α and β, have in common?

A

Both have carboxyl-terminal cytoplasmic tails that are 5 to 12 aa long

85
Q

What are the cytoplasmic regions of the TCR chains too small to do?

A

Transduce signals.

86
Q

What serves as signal-transducing subunits of the TCR complex?

A

CD3 and ζ proteins

87
Q

What is CD3 composed of?

A

Three polypeptide chains, named γ, δ, and ε, arranged in two pairs (γε and δε) - These proteins are homologous to each other and are members of the Ig superfamily

88
Q

What are the major surface molecules of CD4 T cells and APCs involved in T cell activation?

A 
CD4
TCR---Class II MHC
CD3
CD28---B7-1/2
LFA-1---ICAM-1
89
Q

What are the regions of signaling proteins that are phosphorylated and dock other signaling molecules?

A

ITAMs

90
Q

What is the function of CD3 and ζ ?

A

Signal transduction by TCR complex

91
Q

What is the function of CD4 and what is its ligand?

A 
Function: signal transduction
Ligand: class II MHC expressed in APCs
92
Q

What is the function of CD8 and what is its ligand?

A

Function: signal transduction
Ligand: Class I MHC expressed on all nucleated cells

93
Q

What is the function of CD28 and what is its ligand?

A

Signal transduction as a costimulator

B7-1/B7-2 on APCs

94
Q

What is the function of CTLA-4 (CTL antigen 4)? What is its ligand?

A 
Signal transduction (negative regulation)
Ligand: B7-1/B7-2 on APCs
95
Q

What is the function of PD-1 (program death-1) and its ligand?

A 
Signal tranduction (negative regulation) 
Ligand: PD-L1/PD-L2 on APCs, tissue cells and tumor cells
96
Q

What is the function of LFA-1 and its ligand?

A

Adhesion

Ligand: ICAM-1 on APCs and endothelium

97
Q

CD4 and CD8: which one exists as a monomer and the other as a heterodimer?

A

CD4 is a monomer and CD8 is a disulfide-linked heterodimer

98
Q

CD4 is composed of what?

A

Four extracellular Ig-like domains
A hydrophobic transmembrane region
And a highly basic cytoplasmic tail 38 aa long

99
Q

What is CD8 composed of?

A

Two related chains called CD8α and CD8β
Each chain has a single extracellular Ig domain
A hydrophobic transmembrane region
and a highly basic cytoplasmic tail that is about 25 aa long

100
Q

What does CD4 mainly binds to?

A

To class I MHC molecules and also interacts with β2 microglobulin

101
Q

What does the two N-terminal Ig like domains of CD4 protein bind to?

A

The non-polymorphic α2 and β2 domains of the class II MHC

102
Q

What does the cytoplasmic tails of both CD4 and CD8 bind to? What is the purpose?

A

The Src family kinase Lck: helps these proteins to be drawn adjacent to the TCR that contacts the same MHC-peptide complex on the APC

103
Q

What does Lck do?

A

Phosphorylates the tyrosine residues on ITAMs

104
Q

On Ag recognition, what does the TCR complexes cluster with?

A

CD4 or CD8

105
Q

Once the CD4-associated Lck becomes active what does it do?

A

Phosphorylates ITAMs of CD3 and ζ chains

106
Q

Once ζ chains are phosphorlyated, what bind to the phosphotyrosines of the ζ chains?

A

ZAP-70 binds and is itself phosphorylated and activated

107
Q

What does active ZAP-70 then activate?

A

Various adaptors such as LAT

108
Q

What do the activated adaptors become?

A

Docking sites for PLCγ1 and exchange factors that activate Ras and MAP kinases

109
Q

Involving cell survival, where is activated PI3-kinase recruited to and what does it generate?

A

The TCR complex and generates phosphatidylinositol trisphosphate (PIP3) from phosphatidylinositol biphosphate (PIP2)

110
Q

What is PDK1?

A

A PIP3-dependent kinase which phosphorylates and activates a downstream Akt kinase

111
Q

What does activated Akt contribute to?

A

Cell survival by inactivation pro-apoptotic proteins of the Bcl-2 family of apoptotic proteins

112
Q

Where is PKC-0 located in reference to talin in the synapse?

A

PKC-0 is central while talin has a peripheral location

113
Q

What is talin associated with?

A

It is a protein that associates with the cytoplasmic tail of the LFA1 integrin

114
Q

What does PKC0 associate with?

A

The TCR complex

115
Q

What does the immunologic synapse form?

A

A stable contact between an antigen-specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell

116
Q

What does Lck activate upon Ag recognition in the Ras-MAP kinase pathway?

A

ZAP-70

117
Q

What does ZAP-70 phosphorylate after it is activated in the Ras-MAP kinase pathway?

A

membrane-associated adaptor protein LAT

118
Q

What does Lat serve as in the Ras-MAP kinase pathway?

A

The docking site for SH2 domain of Grb-2

119
Q

Once Grb-2 is bound to activated LAT in the Ras-MAP kinase pathway, what does it do?

A

Recruits the Ras GTP/GDP exchange factor called SOS

120
Q

Once the SOS is docked on Grb-2 in the Ras pathway, what does SOS do?

A

Converts Ras-GDP to Ras GTP

121
Q

What does Ras-GTP activates?

A

Directly activates MAP kinase and Raf

Raf then goes to phosphorylate and activate MED-1, which then activates ERK

122
Q

What does ERK do in the Ras pathway?

A

Translocates to the nucleus and phosphorylates Elk (protein)

123
Q

What does Elk in the Ras pathway do?

A

Elk stimulates transcription of c-FOS which is a component of the AP-1

124
Q

What does the Ras cascade activate?

A

AP-1

125
Q

Describe the steps that involve PLCγ1 in T cell signaling

A
  1. activated LAT binds PLCγ1 and it is activated by ZAP-70
  2. Activated PLCγ1 hydrolyzes membrane PIP2 to generate inositol trisphosphate (IP3) and diacyl-glycerol(DAG)
  3. IP3 stimulates an increase in cytosolic Ca ions released from ER
  4. DAG activates enzyme PKC
  5. PKC and cytosolic Ca ions induce numberous cellular responses
126
Q

Multiple signaling pathways converge in Ag-stimulated T cells all leading to what?

A

Transactivation of IL-2 gene

127
Q

What does calcium-calmodulin activate?

A

Nuclear factor of activated T cells (NFAT) and the Ras and Rac pathways which generate AP-1

128
Q

what is important in activating NF-kB?

A

PKC

129
Q

What is NF-kB?

A

Is a p50p60 heterodimer inactivated by IkB

130
Q

How is NF-kB activated?

A

PKC phosphorylates IkB(inhibitor of NF-kB)

131
Q

Where is activated NF-kB translocated?

A

To the nucleus

132
Q

Together, AP-1 and NF-kB do what?

A

regulate gene expression

133
Q

During the classical pathwya for NF-kB induction, what have been demonstrated to be targets of TCR or CD28 signaling?

A

IKKα, IKKβ, IkBα, IkBβ, NF-kB1 p50, RelA p65, c-Rel

134
Q

TCR (signal 1) and CD28 (signal 2) induce different signaling pathways that results in what?

A

The activation of several transcription factors

135
Q

In the nucleus, what does NFAT cooperate with?

A

AP1 and NF-kB to induce gene expression of a productive immune response

136
Q

When TCR engagement occurs in the absence of co-stimulation, what happens?

A

Calcium-mediated signals induce the activation of NFAT only

137
Q

What doe NFAT alone elicit?

A

The expression of a distinct set of anergy-inducing genes

138
Q

What does the products of anergy-inducing genes do?

A

inhibit T - cell function at different levels and induce a status of T-cell unresponsivemenss

Immunology Test II (7 decks)

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