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Immunology 2.0 > Lecture 7: Immune Receptors and Signal Transduction > Flashcards

Lecture 7: Immune Receptors and Signal Transduction Flashcards

1
Q

Primary T cell Deficiency (TCR Signaling)

A
  • CD40 ligand deficiency
  • CD40 deficiency
  • CD3gamma deficiency
  • CD8 deficiency
  • ZAP-70 deficiency
  • Ca++ channel deficiency
  • CD25 deficiency
  • STAT5b deficiency
  • Itk deficiency
  • DOCK8 deficiency
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2
Q

Nuclear receptors are intracellular transcription factors that are activated by ______ that can cross the plasma membrane

A

lipid-soluble ligands (estrogen, progesterone, retinoic acid)

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3
Q

Enzymatic phosphorylation of ___, ___, or ____ in the cytosolic portion of the receptor initiates the signal transduction

A

tyrosine, serine, or threonine

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4
Q

Specific phosphatases usually play a ____ role in signaling transduction

A

inhibitory

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5
Q

Tyrosine Kinase Families

A
  • Src family (c-Src, Lyn, Fyn, and Lck
  • Syk family (Syk and ZAP-70)
  • Tec family (Tec, Btk, and Itk)
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6
Q

SH2 domains bind

A

phosphotyrosine

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7
Q

SH3 binds

A

proline-rich peptides

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8
Q

PH (Pleckstrin homology) domain binds (note the pleckstrin name derives from platelet and leukocyte C kinase substrate and the KSTR string of amino acids)

A

inositol phopholipids (PIP3) or other phosphatidylinosiol-derived lipids

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9
Q

SH2 domains are composed of about ___ amino acids while SH3 domains are composed of about ____ amino acids

A

100 (SH2 domains)

50 (SH3 domains)

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10
Q

The Btk tyrosine kinase recognizes a lipid moiety on the inner leaflet of the plasma membrane termed

A

phosphatidylinositol triphosphate (PIP3) ( note that the other Tec family kinases are Tec and Itk

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11
Q

Do adaptor proteins have catalytic activity

A

No

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12
Q

adaptor proteins contain only _____ interaction domains

A

protein-protein

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13
Q

adaptor proteins are molecular hubs that physically link different enzymes and promote the assembly of complexes of signaling molecules. Ex?

A
  • LAT (linker for the activation of T cells)
  • BLNK (B cell linker)
  • SLP-76 (SH2 domain-containing linker protien)
  • GADS (Grb-2 related adaptor protein downstream of Shc)
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14
Q

____ is an integral membrane protein that functions as an adaptor

A

LAT (lysophospholipid-Acyl-Transferase)

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15
Q

LAT is phosphorylated and recruits ____ and the ____ adaptor

A

Phosphoinositide phospholipase C (PLCgamma) and the GADS adaptor

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16
Q

SLP-76 (proline-rich stretch) associates with GADS via _____ domain and recruits _____ after being tyrosine phosphorylated

A
  • SH3 domain
  • VAV
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17
Q

_____ proteins are guanine nucleotide exchange factors (GEFs) for GTPases that activate actin cytoskeletal rearrangements and transcriptional alterations

A

VAV

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18
Q

phosphorylated ITIMs recuruit

A

tyrosine or inositol lipid phosphatases, which remove phosphate residues from phosphotyrosine moieties or from certain lipid phosphates and thus counteract ITAM-based immune receptor activation

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19
Q

Tyrosine-phosphorylated ITAMs recruit a distinct tyroxsine kinase of the _____ family, which contains tandem SH2 domains that each bind to one of the two phosphorylated YxxL/I motifs of the ITAM

A

Syk/ZAP-70

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20
Q

The inhibitory receptor _____ is found on B cells and myeloid cells

A

FcyRIIB

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21
Q

activating receptors have separate polypeptide chains for recognition and associated signaling polypeptide chains that contain cytosolic _____

A

ITAMs

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22
Q

Inhibitory receptors in the immune system typically have ____ on the cytolsolic portion of the same chain that uses its extracellular domain for ligand recognition

A

ITIMs

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23
Q

FcepsilonRI is what kind of receptor

A

high-affinity activating receptor for IgE

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24
Q

What kind of receptor is FCgammaRIIB

A
  • inihibitory Fc receptor for IgG
  • found on B cells and myeloid cells
25
Q

Signaling downstream of TCRs and BCRs is characterized by a similar sequence of events consisting of:

A
  • Receptor ligation typically involves the clustering of receptors by multivalent ligands and results in activation of an associated Src family kinase.
  • receptor ligation may also induce the unfolding of the cytoplasmic tail of a polypeptide chain that is part of the receptor. The unfolding event (or conformational change) may allow previously hidden tyrosine residues of a cytosolic ITAM motif to become available for phosphorylation by a Src family kinase
  • The activated Src family kinase phosphorylates available tyrosines in the ITAMs of signaling proteins that are part of the receptor complex
  • The two phosphorylated tyrosines in a single ITAM are recognized by a Syk family tyrosine kinase that has tandem SH2 domains that each bind to an ITAM phosphotyrosine
  • Recruitment of the Syk family kinase to the phosphorylated ITAM results in the activation of this tyrosine kinase and the subsequent tyrosine phosphorylation of adaptor proteins and enzymes that activate distinct signaling pathways downstream of the immune receptor
26
Q

The TCR complex has ___ signaling chains and ___ ITAMs, and increasing numbers of ITAMs may be phosphorylated with stronger or prolonged bidning of antigen to the TCR

A

6 signaling chains

10 ITAMs

27
Q

a coreceptor is a _________ signaling protein on a lymphocyte that can facilitate Ag receptor activation

A

transmembrane

28
Q

The coreceptor with its signaling enzymes can

A

increase ITAM phosphorylation and activation fo the Ag receptor

29
Q

Coreceptor on B cells

A

Complement receptor tyep 2 (CR2/CD21)

30
Q

key inhibitory receptors in T cells

A

CTLA-4 and PD-1

31
Q

Inhibitory receptors in B cells

A

CD22 and FcgammaRIIB

32
Q

Prototypic costimulatory receptor on T cells

A

CD28 (which is activated by costimulatory molecules B7-1 (CD80) and B7-2 (CD86) ligands induced on APCs as a resulte of their exposure to microbes)

33
Q

What is the difference between costimulation and coreceptors

A

unlike coreceptors, costimulatory receptors do not recognize components of the same ligands as do antigen receptors; signal outputs downstream of costimulatory receptors are integrated with the signals derived from the antigen receptor, and these signals cooperate to fully activate lymphocytes

34
Q

The TCR complex consists of ______, ____, and ____ the association of these proteins with one another is mediated by

A
  • The TCR complex consists of
    • Alphabeta TCR non-covalently linked to CD3 and zeta proteins
  • The association of these proteins with one another is mediated by charged residues in their transmembrane regions
35
Q

the alpha and beta chains of the TCR have carboxyl-terminal cytoplasmic tails that are ___ to ___ amino acids long and there for are

A

5 to 12 amino acids long and are therefore too small to transduce signals, CD3 and zeta proteins serve as signal-transducing subunits of TCR complex

36
Q

structure of CD4

A
  • Four extracellular Ig-like domains
  • a hydrophobic transmembrane region
  • a highly basic cytoplasmic tail 38 amino acids long
37
Q

Structure of CD8 coreceptors

A
  • is composed of two related chains called CD8alpha and CD8beta
    • CD8alpha and CD8beta have:
      • a single extracellular Ig domain
      • a hydrophobic transmembrane region
      • a highly basic cytoplasmic tail that is about 25 amino acds long
38
Q

CD8 coreceptors interact with

A

MHC class I and also Beta2 microglobulin

39
Q

CD4 and CD8 are T cell coreceptors that bind to ________ of MHC molecules and facilitate signaling by the TCR complex during T cell activation

A

polymorphic regions

40
Q

On ag recognition, TCR complex cluster with CD4 or CD8. CD4/CD8-associated Lck becomes active and ____________. Then ZAP-70

A
  • Lck: phosphorylates ITAMs of CD3 and zeta chains
  • ZAP-70: binds to the phosphotyrosines of the zeta chains that become self-phosphorylated and activated. It then activates (phosphorylates) various adaptor proteins such as LAT
41
Q
A
42
Q

Ligation of the TCR with Ag and CD29-CD80/CD86 costimulation results in

A

rapid activation fo phosphoinositide-3-kinase (PI3K)

43
Q

What is the funciton of PI3K (phosphoinositide-3-kinase)

A

converts phosphatidylinositol bisphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3)

44
Q

what is the function of PDK1

A

PDK1, a PIP3-dependent kinase, phosphorylates and activates a downstream Akt kinase

45
Q

What is the function of activated Akt

A

contributes to cell survival by inactivating pro-apoptotic proteins of the Bcl-2 family of apoptotic proteins

46
Q

List the steps in the Ras-pathway

A
  • upon ag recognition, Lck activates ZAP-70
  • ZAP-70 phosphorylates/activates membrane-associated adaptor proteins LAT
  • activated LAT binds Grb-2 adaptor protein
  • Grb-2 docks the GTP/GDP exchange factor SOS
  • SOS converts Ras-GDP to Ras-GTP
  • Ras-GTP activates MAP kinase (MEK-1) and ERK
  • ERK activates transcription factor AP-1
47
Q

PLCgamma 1 in T cell signaling

A
  • activated LAT adaptor protien binds PLCgamma-1
  • The ZAP-70 activates PLCgamma-1
  • activated PLCgamma-1 hydrolyzes membrane PIP2 and generates IP3 (inositol trisphosphate) and DAG (diacyl-glycerol)
  • Produced IP3 stimulates an increase in cytosolic Ca2+ released from the ER
  • Then, DAG activates the enzyme PKC
  • Then, PKC and Ca2+ ions induce numerous cellular responses
48
Q

what are the three major groups of MAP kinases in mammalian cells

A
  • ERK (extracellular signal-regulated protein kinases)
  • p38 MAP kinases
  • JNK, c-Jun NH2-terminal kinases
49
Q

ELK is a transcritpion factor that activates transcription of transcriptional factor ____

A

Fos

50
Q

The p38 and JNK MAP kinases are activated by ____ from the Rho fmaily GTPases

A

Rac-GTP

51
Q

Protein Jun in combination with Fos forms the

A

AP-1 early response transcription factor

52
Q

The alternative Pathway of NF-kBeta pathway

A
  • is engaged by a restricted set of cell-surface receptors
    • LTbetaR
    • BAFF-R
    • CD40
  • This pathway culminates in the activaiton of IKKalpha
  • IKKAlpha directly phosphorylates RelB/p100 (NF-kBeta 2/p100)
  • phosphorylation induces a partial proteolysis of p100 to p52 by the proteasome
  • the p52 protein dimerizes with RelB to translocate into the nucleus
53
Q

NFAT is a transcrition factor required for the expression of genes encoding

A
  • IL-2
  • IL-4
  • TNF
  • and other cytokines
54
Q

NFAT is activated by

A

calcium-calmodulin-dependent phosphatase calcineurin

55
Q

anergy can be induced by substimulatory levels of Ags in the absence of

A
  • costimulatory signal provided by soluble cytokines
  • interactions between costimulatory receptors on T cells and counter-receptors on APCs
56
Q

when TCR engagement (signal 1) occurs in the absence of co-stimulation, calcium-mediated signals induce the activation of NFAT only. NFAT alone elicits

A

the expression of a distint set of anergy-inducing genes

57
Q

CD3 is composed fo three polypeptide chains (__, ___, and ___) arranged in two pairs

A
  • gamma, delta, epsilon
  • two pairs ( gammaepsilon and deltaepsilon
58
Q

what is Talin is a protein associated with

A

a protein associated with LFA-1

59
Q

PKC-sigma is associated with the

A

TCR complex

Immunology 2.0 (25 decks)

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