6 - Immune Receptors and Signal Transduction

Question 1

Cytokines

Answer 1

Low weight regulatory molecules (proteins or glycoproteins) secreted by immune cells and various other cells in response to stimuli

Question 2

Ways of cytokine signalling

Answer 2

• Autocrine (same cell)
• Paracrine (close proximity)
• Endocrine (long distance)

Question 3

Major categories of signalling receptors in the immune system

Answer 3

• a receptor that uses a non-receptor tyrosine kinase
• a receptor tyrosine kinase
• a nuclear receptor that binds its ligand and can then influence transcription
• a seven-transmembrane G protein–coupled receptor (GPCR)
• Notch, which recognizes a ligand on a distinct cell and is cleaved, yielding an intracellular fragment (IC Notch) that can enter the nucleus and influence transcription of specific target genes.

Question 4

Non receptor tyrosine kinase-based receptors

Answer 4

• Regulate cell growth, proliferation, differentiation, adhesion, migration and apoptosis
• Mediate cytokine responses

Question 5

Cytosolic signalling phase of NRTK

Answer 5

• The NRTK phosphorylates a key tyrosine residue on the cytoplasmic tail of the receptor
• The phosphotyrosine-containing receptor tail is able to recruit a downstream enzyme that is activated once its recruited
• Modifies a specific transcription factor that is located in the cytoplasm

Question 6

Nuclear signalling phase of NRTK

Answer 6

• This modified transcription factor enters the nucleus and binds to a specific site in the promoter or in some other regulatory region of target genes and thus facilitates their expression
• Cytokines are produced by receptor-expressing cell

Question 7

SRC family kinases

Answer 7

Immunologically important family of nonreceptor tyrosine kinases

Question 8

c-SRC

Answer 8

• Cellular homolog of the transforming protein of the Rous sarcoma virus
• c-SRC contains several distinct domains, two of which, called SRC homology 2 (SH2) and SRC homology 3 (SH3) domains, mediate binding to other signaling proteins

Question 9

FcγRIIB

Answer 9

Inhibitory receptor found on B cells and myeloid cells

Question 10

Activating and inhibitory Immune receptors

Answer 10

• Immune receptors that activate immune cells have separate polypeptide chains for
  recognition, and associated polypeptide chains that contain cytosolic ITAMs (immunoreceptor tyrosine activation motif)
• Inhibitory receptors in the immune system typically have ITIMs on the cytosolic portion of
  the same chain that uses its extracellular domain for ligand recognition

Question 11

Structure of T cell receptor

Answer 11

• The antigen-binding portion of the TCR is formed by the Vβ and Vα domains.
• The hypervariable segment loops that form the
  peptide-MHC binding site are at the top

Question 12

TCR complex

Answer 12

• The CD3 and ζ proteins are noncovalently associated with the TCR αβ heterodimer to form the TCR complex
• When the TCR recognizes antigen, the associated
  proteins transduce the signals that lead to T cell activation

Question 13

CD3 and ζ proteins

Answer 13

• Identical in all T cells regardless of specificity, showing their role in signalling and not antigen recognition
• Required for surface expression of the complete receptor complex on T cells

Question 14

Which cells express CD3

Answer 14

T cells

Question 15

Other T cell receptors (besides TCR)

Answer 15

• CD3
• CD4
• CD8
• CD28
• CTLA-4
• PD-1
• LFA-1

Question 16

CD3

Answer 16

• Signal transduction by TCR complex
• No ligand

Question 17

CD4

Answer 17

• Signal transduction
• Ligand: Class II MHC expressed on APCs

Question 18

CD8

Answer 18

• Signal transduction
• Ligand: Class I MHC on all nucleated cells

Question 19

CD28

Answer 19

• Signal transduction (costimulation)
• Ligand: B7-1/B7-2 on APCs

Question 20

CTLA-4

Answer 20

• Inhibition
• Ligand: B7-1/B7-2 on APCs

Question 21

PD-1

Answer 21

• Inhibition
• has an immunoreceptor tyrosine-based switch motif (ITSM) in its cytoplasmic domain
• Ligand: PD-L1/PD-L2 on APCs, tissue cells and tumor cells

Question 22

LFA-1

Answer 22

• Adhesion
• Ligand: ICAM-1 on APCS and enothelium

Question 23

Early tyrosine kinase phosphorylation events in T cell activation

Answer 23

• On antigen recognition, there is clustering of T cell receptor complexes with coreceptors
• CD4-associated LCK becomes active and phosphorylates tyrosines in the ITAMs of CD3 and ζ chains
• ZAP70 binds to the phosphotyrosines of the ζ chains and is itself phosphorylated and activated.
• Active ZAP70 then phosphorylates tyrosines on
  various adaptor molecules (such as LAT)

Question 24

The immune synapse
supramolecular activation cluster (SMAC)

Answer 24

• When the TCR complex recognises MHC associated peptides on an APC, several T cell surface proteins and intracellular signalling
  molecules are rapidly mobilized to the site of T cell–APC contact
• PKC is a protein kinase involved in signal transduction
• Integrins LFA-1 and talin function to stabilise binding of the T cell to antigen presenting cell, APC

Question 25

MicroRNAs (miRNAs)

Answer 25

• miRNAs are small noncoding RNAs that are transcribed from DNA but are not translated into proteins
• Act to inhibit gene expression
• One strand of the miRNA can pair with a complementary sequence in a number of cellular messenger mRNAs

Question 26

B cell receptor complex

Answer 26

Membrane immunoglobulin (IgM and IgD) on the surface of mature B cells is associated with the invariant Igβ and Igα molecules, which contain ITAMs in their cytoplasmic tails that mediate signalling functions

Question 27

Cytoplasmic tail of membrane IgG

Answer 27

Contains a Ig tail tyrosine (ITT) motif that helps amplify B cell receptor signalling in memory B cells.

Question 28

Antigen-induced cross-linking of membrane immunoglobulin (Ig) on B cells

Answer 28

• Clustering and activation of SRC family tyrosine kinases and tyrosine phosphorylation of the ITAMs in the cytoplasmic tails of the Igα and Igβ molecules
• Leads to docking of SYK and subsequent tyrosine phosphorylation events
• Signaling cascades follow these events leading to the activation of transcription factors
• Signal transduction pathways are similar to those
  described in T cells

Question 29

Role of complement in B cell activation

Answer 29

• B cells express a complex of the CR2 complement receptor, CD19, and CD81
• Microbial antigens that have bound the complement fragment C3d can simultaneously engage both the CR2 molecule and the membrane immunoglobulin (Ig) on the surface of a B cell
• This leads to the initiation of signalling cascades from both the B cell receptor complex and the CR2 complex:
• The response to C3d-antigen complexes is greatly enhanced compared with the response to antigen alone.

Question 30

Role of the ubiquitin ligase CBL-b in terminating T cell responses

Answer 30

• facilitates the ubiquitination of CD3, ZAP70, and other proteins of the TCR complex
• These proteins are targeted for proteolytic degradation

Question 31

Extracellular and intracellular portions of cytokine receptors

Answer 31

All cytokine receptors consist of one or more transmembrane proteins whose extracellular portions are responsible for cytokine binding and whose cytoplasmic portions are responsible for initiation of intracellular signaling pathways

Question 32

RNA induced silencing complexes (RISC)

Answer 32

In the cytosol, pre-miRNAs are processed by endoribonuclease Dicer into short double-stranded miRNAs, 21 to 22 base pairs in length, which associate with several proteins, including Argonaute, to form a RISC

Question 33

What does ligation of receptors for type 1 and 2 cytokines result in

Answer 33

• Activation of an associated JAK tyrosine kinase
• Phosphorylation of the receptor tail
• Recruitment of an SH2 domain, containing activator of transcription (STAT) to the receptor

Question 34

JAK-STAT signalling

Answer 34

• Many cytokine receptors use non-receptor tyrosine kinases called JAKs to phosphorylate transcription factors called STATs
• The recruited STAT is activated by JAK phosphorylation, dimerizes, enters the nucleus, and turns on the expression of cytokine target genes

Question 35

CD3 structure

Answer 35

• CD3 γ, δ, and ε and the ζ homodimer.
• The CD3 chains each contain one ITAM, whereas each ζ chain contains three ITAMs