T lymphocytes Flashcards
Explain the structure of the T cell receptor
- analogous to antibody structure ○ Variable region interacts with antigen ○ Short cytoplasm tail ○ Alpha and beta components ○ Small subset of gamma and delta chains - All express CD3 - Fab: antigen binding fragment - Fc: crystallizable fragment
How do T cells bind antigens?
- Charged residues in transmembrane region of alpha and beta chains interact with oppositely charged residues in transmembrane regions of CD3 polypeptides
○ Have much longer cytoplasmic tails with motives containing tyrosine residues
○ When TCR meets antigen it phosphorylates tyrosine which triggers several chemical cascades.
○ ITAM: immunoreceptor tyrosine based activation motif
How does T cell recognize antigen?
- CD4 see MHC Class 2
- CD8 express MHC Class 1
- Coreceptors bind to relevant MHC
What do Th do?
- Secrete cytokines
- Recruit effector
- Activate macrophages, CTL, B cell
- Split into Th1 and Th2 depending on what cytokine they release
What do CTL do?
- Kill target cell
- Induce apoptosis in target cell
How do T cells mature?
- Progenitor cells move to thymus
- Begin as immature lymphocytes in cortex
- As develop move towards medulla where mature
- At thymus have no TCR, CD4, CD8
- See which MHC recognizes depending on that either CD4 or CD8
How does gene rearrangement occur?
- Beta chain is rearranged
- Alpha chain is rearranged
- Proper alpha-beta TCR is formed
- Start expressing both receptors
- Final decision
In what order are the chains rearranged?
- Beta chain has VDJ
○ Rearranged first
- Alpha has VJ
○ Rearranged second
○ Diversity achieved by selecting from gene
segments availableWhat checkpoints are there to ensure the cell is functional?
1st checkpoint: beta chain rearranged if functional moves on to next stage
2nd checkpoint: does it recognize self MHC
- If it doesn’t it’s useless
- If binds too tightly could be dangerous
- Something in between is useful
- Only 5% of lymphocytes survive selection
Define MHC
- Display sample of internal contents of cells at cell surface
- Markers of self
- Always present peptides, even in absence of infection
- Present antigens to T lymphocytes
What is the structure of MHC1?
- A is heavy
○ A1, A2, A3 - B2 microglobulin is light (associates non covalently with heavy chain)
- Domains linked by transmembrane region
- Peptides bond between a1 and a2 domains
- transplantation antigen
What is the structure of MHC2?
Class 2: similar but 2 polypeptides equal in size and both transmembrane
- Alpha and beta chain
- 2 transmembrane regions
- CD4 and CD8 peptide binding region between a1 and b1
- End of peptides often sticks out of binding site
- regulatory antigen
What is the antigen specific interaction in MHC?
- Hypervariable loops interact with peptide MHC complex
- TCR-peptide-MHC complex
How does MHC bind antigens?
- certain position on MHC that are relatively conserved with peptide binding motif
○ Binding pockets and anchor residues - Can be recognized by antigen receptor
- small diversity so needs to bind large number of different peptides but have some specificity
What is HLA?
Human Leukocyte antigen: encodes human MHC
How are MHC1 and MHC2 expressed?
- polygenic and several loci
- Co dominant
- MHC 1: nearly all cells express it although levels vary depending infection or by cytokines
- MHC 2: only professional APC express it
What are the types of APCs?
see notes
How are antigens classified?
- endogenous antigen: (synthesised in cytoplasm) to CD8/MHC1
- exogenous antigen: (captured from external environment) to CD4/MHC2
How do APC present antigens to MHC1?
MHC1 (endogenous)
- Viral proteins in cytoplasm chopped up by proteasome to make peptides
- move into ER to associate with new Class 1 heavy chain via transporter associated with antigen processing (TAP)
- MHC 1 moves into ER
- Complex: heavy chain, beta 2 microglobulin, peptide
- Once all 3 correctly folded goes via Golgi to cell surface for recognition by CD8 and T lymphocytes
How do APC present antigens to MHC2?
MHC2 (exogenous)
- Class 2 endocytosed and processed into peptides in endocytic vessels
- Move into ER
- Associate with invariant chain
- Directs class 2 that haven’t been loaded yet via Golgi into endocytosis vesicles
- Small fragment derived from invariant chain (CLIP peptide)
- Swap CLIP peptide for antigenic peptide that have been processed initially
- Load antigen peptide onto MHC 2 and move to surface receptor form recognition
Which part do coreceptors bind to
invariant part of MHC
- increase avidity
