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(J) Immunology Test 2 > Lecture 8 - Immune Receptors and Signal Transduction (part I) > Flashcards

Lecture 8 - Immune Receptors and Signal Transduction (part I) Flashcards

1
Q

What is the general mechanism of signal transduction?

L8 S6

A
  • ligand binds extracellular domain causing conformational change
  • multiple receptors cluster around ligand and cross-link
  • the clustered, conformationally changed receptors cause a change in the cytoplasmic portion and interact with other signaling molecules
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2
Q

What are the main types of kinases used in signal transduction?

L8 S8

A

Tyrosine kinase:
-phosphorylates tyrosine residues

Serine/threonine kinases:
-phosphorylates serine and threonine residues

Lipid kinases:
-phosphorylates certain lipids

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3
Q

What do phosphatases do and what is their primary role in signal transduction?

L8 S8

A

Removal of phosphate group which is typically inhibitory

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4
Q

What protein modifications can be made that affect signal transduction and what affect do these changes typically have?

L8 S9

A

Phosphorylation:
-typically activates signal

Ubiquitinates:
-targets protein for degradation

Addition of lipid component:
-typically targets for localization in plasma membrane

Acetylation/methylation (of histones):
-regulates gene expression and DNA replication/recombination

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5
Q

What is the structure and function of a signaling protein?

L8 S12

A

Consists of interaction domain (binds ligand) and catalytic domain (generates signals).

Binding of specific ligand to interaction domain allosterically activates otherwise inactive catalytic domain

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6
Q

What are the different families of tyrosine kinases?

L8 S13

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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7
Q

What are are the general structures found in each family of tyrosine kinase families?

L8 S14-15

A

Src:

  • SH 1 (kinase domain)
  • SH2 domain (binds phosphotyrosine)
  • SH3 domain (binds proline rich protein
  • SH4 domain (myristic acid component used for insertion into inner membrane)

Syk:

  • SH 1 (kinase domain)
  • SH2 domain (binds phosphotyrosine)

Tec:

  • SH 1 (kinase domain)
  • SH2 domain (binds phosphotyrosine)
  • SH3 domain (binds proline rich protein
  • PH domain (phospholipid recognition) (PIP3 in Btk)
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8
Q

How is Src function regulated and what two amino acid residues are crucial to regulation?

L8 S16

A

Tyr416 and Tyr527 are crucial

Phosphorylation of Tyr 416 activates Src by making the P-Tyr416 accessible to substrates.
This Tyr can be autophosphorylated

Phosphorylation of Tyr527 inactivates Src by causing it to create an inaccessible bundle by associating with SH2 domain.

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9
Q

What are the properties of an adapter protein in signaling pathways?

L8 S18

A

Noncatalytic

Only from protein-protein interactions

Link and promote different signaling complex formation:

  • LAT (Linker for the Activation of T cells)
  • BLNK (B cell LiNKer)

Can contain several:

  • SH2 domain (binds phosphotyrosine)
  • SH3 domain (binds proline rich protein)
  • Tyr residues that can bind other SH2 domains
  • Proline-rich regions that can bind other SH3 domains
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10
Q

What is the mechanism by which T cells are activated by signal transduction?
What molecules are involved?

L8 S20

A
  • phosphorylated LAT (Linker for the Activation of T cells) attracts PLCγ and GADS
  • SLP-76, which contains a proline-rich region, binds a SH3 domain on GADS
  • VAV is recruited after being Tyr-phosphorylated
  • VAV is a GEF (guanine nucleotide exchange factor) that causes actin cytoskeleton rearrangements and transcription changes
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11
Q

What is the structure and function of TCR complexes in signaling pathways?

L8 S22

A

Consists of:

  • an αβ TCR heterodimer
  • two CD3 heterodimers (εγ and εδ)
  • a ζ homodimer

αβ TCR heterodimer binds MHC presented protein while CD3 and ζ dimer act as signal transducers

Association of dimers is due to charged residues in their transmembrane domains.

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12
Q

What is the structure and function of CD4 and CD8 in signaling pathways?

L8 S18

A

CD4 (monomer):

  • 4 extracellular Ig-like domains
  • transmembrane region
  • basic, cytosolic tail

CD8 (αβ dimer):

  • single extracellular Ig-like domain
  • transmembrane region
  • basic cytosolic tail
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13
Q

What are ITAMs and ITIMs?

L8 S24

A

ITAM (immunoreceptor tyrosine-based activating motif):
-consists of Tyr-X-X-Lys sequence with the Tyr being able to be phosphorylated

ITIM (immunoreceptor tyrosine-based inhibitory motifs)

They are typically associated with the cytosolic tails of signaling molecules

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14
Q

What are FcεRI and FcγRIIB?

L8 S24

A

FcεRI

  • activating receptor for IgE (epsilon for IgE)
  • contains ITAM

FcγRIIB

  • inhibiting receptor for IgG (gamma for IgG)
  • contains ITIM
  • found on B cells and myeloid cells
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15
Q

How are ITAMs associated with TCR complex’s T cell function?

L8 S25

A

TCR complex contains 10 ITAMS on 6 different signaling chains (CD3 and ζ dimer)

The stronger the affinity of TCR for Ag more ITAMs are phosphorylated.

Weak TCR signals are required for positive selection of T cells in thymus.

Strong TCR signals lead to negative selection of T cells in thymus.

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16
Q

Describe the steps in the TCR-dependent cascade.

L8 S27

A
  • TCR associates with MHC class II/I
  • CD4/8 engages MHCII/I and activates Lck (Src family)
  • Lck phosphorylated ITAMs to activate ZAP-70 (Syk family)
  • ZAP-70 phosphorylates LAT (linker … T cell) which activates PLC-γ and ras/rac
  • PLC-γ cleaves PIP2 to form IP3 and DAG
  • DAG + calcium activates PKC/IKK (protein kinase C); PKC phosphorylates IκΒ targeting it for ubiquitination causing NFκB to migrate into nucleus
  • IP3 + calcium activates calcinurin which activates NFAT (nuclear factor of activated T-cells)

-ras/rac cause phosphorylation cascade which activates AP-1 family transcription factor that migrate into the nucleus

17
Q

What is anergy, what causes it, and how can it be corrected?

L8 S30

A

T cell unresponsiveness to Ag stimulation caused by reduced IL-2 production.

Exogenous IL-2 production can reverse this.

Can be stimulated by the ABSENCE of:

  • CD28:CD80/86 costimulatory receptors on T cells/APCs
  • stimulators cytokines
18
Q

What are the main transcription factors for T cell activation and what pathways stimulate their production?

L8 S31

A

TCR pathway only:

  • NFAT
  • results in anergy

TCR with CD28:CD80/86:

  • NF-κB
  • AP1
  • NFAT

CD28:CD80/86 only:
-none

19
Q

What is the immunologic synapse and how is it formed?

L8 S34

A
  • TCR weakly associates with pMHC class II/I
  • TCR:MHC complex is stabilized by CD4/8
  • LFA-1:ICAM-1 complexes form and move away TCR:MHC:CD4/8 complex
  • CD28:CD80/86 complexes form and move towards TCR:MHC:CD4/8 complex
20
Q

What are the the TCR accessory molecules, their function, and their ligand?

L8 S36

A

Accessory molecule : function : ligand

  • CD3 : signal transduction : none
  • ζ : signal transduction : none
  • CD4 : signal transduction : MHC class I
  • CD8 : signal transduction : MHC class II
  • CD28 : signal transduction (costimulation) : CD80/86 or B7-1/2
  • PD-1 : signal transduciton (negative regulation) : PD-L1/2
  • LFA-1 : adhesion : ICAM-1

(J) Immunology Test 2 (9 decks)

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