T Cells And MHC

Question 1

Outline TCR

Answer 1

• Equivalent of antibody on T cells
• One heterodimer (half antibody)
• Two chains are alpha and beta or gamma and delta
• Each chain has a variable and constant region
• TCRs remains on surface of T cells- not shed into blood like antibodies
• Evolutionarily homologous to antibodies- derived from same ancestral gene

Question 2

How is TCR diversity generated?

Answer 2

Occurs in thymus not bones marrow
• Multiple germ line genes
• V-J and V-D-J recombination
• recombinatorial inaccuracies
• N-nucleotide addition
• chain recombination
• NO Somatic hypermutation

Question 3

What’s the difference between B and T cells?

Answer 3

• TCR recognises small peptides with no intrinsic structure, held by MHC molecules (to protect from proteolytic enzymes)
• Antibodies recognise the shape of part of an antigen
• T cells can therefore recognise smaller parts of broken down pathogens when microbes are created or broken down

Question 4

Outline MHC

Answer 4

Major histocompatibility complex molecules
• made up of stalk part (2 beta pleated sheets like antibodies), and receptor part (1 beta pleated sheet and 2 alpha helices on either side)
• Hold peptide in such a way that top of peptide is visible but is deeply embedded
• Major factor in transplant rejection
• Most of MHC class 1 molecule is made up of 1 chain, but one of the stalk’s beta-pleated sheets is a separate chain (beta-2-microglobulin)
• We only have ~6 MHC molecules so binding can’t be too sensitive to aa sequence-> bonds form with end of peptide not middle or side chains
• Bottom of MHC molecule has pockets for side chains- will only carry certain peptides

Question 5

Outline TCR binding of MHC and peptide

Answer 5

• Alpha helices (loops) on MHC and TCR bind
• Middle loops most important for specificity
• Interaction with antigen weaker than that of antibodies to allow T cells to move away after recognition

Question 6

Outline the genetics of MHC (HLA) complex I

Answer 6

• Chromosome 6
• Classical class I and II peptide binders:
- class I- A, B & C- each diff MHC, one chain
- class II- DP, DQ & DR- made up of two chains
• A B C DQ DP DR more polymorphic than any other locus
• nomenclature- name Each allele, e.g. HLA-DQ4,-DQ18

Question 7

Outline exogenous processing of the two pathway model of antigen processing

Answer 7

CD4: class II MHC
• MHC II made in ER with invariant chain, sugars added in Golgi
• Peptides taken up and broken down in protease-containing endosome
• MHC II meets with peptide loading compartment, chaperoned by invariant chain which is cleaved and replaced by peptide
• Complex released to cell surface

Non-selective processing- self peptides will bind MHC and be displayed

Question 8

Outline endogenous processing of the two pathway model of antigen processing

Answer 8

CD8: class I MHC
• MHC I made in ER
• Peptides produced by cell in cytoplasm (eg virus)
• Peptides recognised by proteasome and delivered to ER by TAP (transporter of antigen peptide) across ER membrane
• Complex delivered to cell membrane by Trans-Golgi vesicle

Allows infected cells to be recognised as antibodies can’t recognise viruses once inside cells
Also non-selective- Most MHC molecules carry self peptides

Question 9

What are CD3 molecules?

Answer 9

Signalling complex that transduces signal from TCR into cell causing differentiation
(Like Igβ and Igα for B cells)

Question 10

Outline costimulatory molecules

Answer 10

Binding of T cell to target requires secondary attachment:
• E.g. CD8 binds MHC1 regardless of peptide
• LFA-1 on T cell binds ICAM-1 ensuring the APC and T cell are stuck together long enough to interact
• CD28/CTLA4 on T cell binds CD80/86 on APC