Lecture 13; Immune cell receptors

Question 1

What can immune cell receptors be divided into?

Answer 1

MYELOID CELLS (innate)

LYMPHOID CELLS

Question 2

What are the myeloid cell receptors?

Answer 2

1. Fc Receptors
2. TLR (Toll Like Receptors)
3. Other innate receptors such as mannose receptors

Question 3

What are the lymphoid cell receptors?

Answer 3

1. B cells – Immunoglobulin M
2. T cells – T cell Receptors
3. NK cells – NK inhibitory and activating receptors

Question 4

Describe the Fc receptor

Answer 4

• Many forms but all have Ig-domains
• Binds to the effector (Fc) region of IgA, G, D, M or E.
• Low affinity. Only binds immune complexes (multiple AB with antigen, avidity reaction).

Question 5

What are some examples of Fc receptors;

Answer 5

• FcγRI, II, III bind IgG subtypes.
• FcεR binds IgE on mast cells. Atopic allergy.
• FcαR binds IgA (gut)

Question 6

What are ALL Fc receptors linked to?

Answer 6

• Linked to adaptor proteins that contain ITAM motifs.

Question 7

What are Fc receptors essential for?

Answer 7

• Essential for Ig mediated phagocytosis.

Question 8

Describe B Cell receptor;

Answer 8

• IgM expressed on all naive B cells from the bone marrow.
• Has a transmembrane domain.
• Associates with Igα and Igβ molecules possessing ITAM motifs.

Question 9

What does the activation of the BCR require?

Answer 9

• Activation requires cross-linking of BCR by multivalent antigen.
  Binds Syk kinase. Initiates a phosphorylation cascade.
  • BCR is also associated in larger complex of CD19, TAPA and
  CD21 (CR2) essential to signalling.

Question 10

Write some notes on the Ta/b variant receptor;

Answer 10

1. α/β TcR must develop in the thymus.
2. α/β cells are either CD4 or CD8 and found in blood and lymphoid organs
3. β -chain gene rearrangement dependent on γ gene silencer. All α/β T cells start off as γ/δ T cells
4. α/β knockout mice still have some protection

Question 11

Write some notes on the Td/g variant receptor;

Answer 11

1. γ/δ T cells can develop independently of thymus.
2. γ/δ T cells found in sites around the body such as skin IEL.
3. γ chain gene rearranges before β-chain gene. Suggests it is a more primordial receptor.
4. γ/δ knockout mice are susceptible to mycobacterial infections

Question 12

Whats an ITAM?

Answer 12

Immunoreceptor-based Tyrosine Activation Motif Found on cytoplasmic domains of TcR/BcR/FcR Binds Src family kinases

Only on the Z chain, and the length of time spent p/ph them (total p/ph) determines the strength of reaction with self and what happens to the developing T cells

Question 13

What happens after ITAM activation?

Answer 13

PLC-γ

PIP2 -> DAG and IP3

Question 14

What does DAG do?

Answer 14

DAG activates PKC-θ

PKC-θ activates NFkB

Question 15

What does IP3 do?

Answer 15

• IP3 increases Ca2+
  • Ca2+ binds Calmodulin
  • Activates Calcineurin phosphatase
  • Calcineurin de-phosphorylates NF-ATc

NFAT is primary driver of T cell response (Cyclosporin inhibits this)

Question 16

What does GEF do?

Answer 16

Guanine exchange factors (GEF) activate Ras
• Ras activates MAP kinase cascade
• MAP kinase activates c- Fos component of AP-1

Question 17

What do the three arms of activation in the T cells do?

Answer 17

Nuclear translocation of NF-AT,NF-κB and AP-1 to induce specific gene transcription, proliferation and differentiation

Question 18

What do NK receptors recognise?

Answer 18

NK cells are a population of potent lymphoid cells with receptors that recognise non- classical MHC (HLA-C, HLA-G and HLA-E) among others

Most NK cell receptors are termed INHIBITORY receptors.

Question 19

What do NK receptors do?

Answer 19

Most NK cell receptors are termed INHIBITORY receptors.

They actively PREVENT cytolytic killing when triggered by their ligand such as HLA-E.

In the absence of MHC on the target, no inhibition and killing.

Question 20

What are the NK receptors coupled wiht?

Answer 20

Inhibitory receptors are coupled to adaptor molecules with ITIM motifs.

Some NK receptors are activating. They recognise specific ligands associated with cell stress or infection.

NK cells can express both inhibitory and activation receptors on the same cell.

The default response is inhibition.

This must be overridden by activation signal Role is surveillance of cells lacking classical MHC.

Question 21

How do NK cells compete for activation?

Answer 21

NK inhibitory receptors (KIR) mediate SHP1 mediated dephosphorylation that directly competes with the TcR driven phosphorylation.

Question 22

Summerise the TCR a/b variant;

Answer 22

• Classical MHC class I and class I
• CD4 or CD8
• Part of the CD3 complex
• Peptide antigens
• CD3 associated
• ITAMs on ζ-chain
• Lck and Zap70 kinases

Question 23

Summerise the TCR g/d variant;

Answer 23

• CD1 ligand
• CD4 or CD8 or not
• Part of the CD3 complex
• Non-peptide antigens e.g. LAM
• Limited peripheral repertoire

Question 24

Summerise the NK receptors;

Answer 24

• C-type or Ig like
• Non-classical MHC HLA-G, E
• Many different types
• Inhibitory and activating
• Non-polymorphic
• ITIM motifs – inhibitory signal
• SHP-1 phosphatase

Question 25

Summerise the BCR;

Answer 25

• Membrane IgM
• BCR complex CD19, CD21,
TAPA1
• Recognises soluble antigen –
cross-linking
• ITAMs on Igα and Igβ
• Syk, Fyn,Blk, Lyn kinases

Question 26

Summerise the FcR;

Answer 26

• Bind Fc domains of Ig
• Multiple receptors for each class
• No consistent binding mode
• Cross-linking by immune complex
• ITAM receptors