Antigen presentation Flashcards
Challenges for TCR system
Must be presented by other cells
Few T cells express correct TCR (must circulate to find)
Must activate correct subtype of T cell
Activated T cells must navigate back to infection site
TCR vs antibodies
MHC+peptide:TCR
Antigen:antibody
Both highly specific binding with wide variety via recombination
Antibodies both on membrane of B and circulating
TCR requires
- presentation from another cell
- recognition of TCR, peptide and costimulation
- harder to monitor and measure
Constitutive MHC expression
Every peptide constitutively expressed with MHC I
Every cell in body
Usu 8-9 amino acid sequences - still provide enough information for specificity and recognition of foreign
MHC I pathway
Intracellular proteins -> CD8 T cells
- Both normal self proteins and intracellular (viral) pathogens
- Constitutive process in all cells
Expressed on all cells - ex CD8 can recognize infected cells
Only “professional” APCs can provide costimulation to prime T cells for response
MHC I presentation
Proteins -> proteasome -> ER (loaded onto MHC) -> Golgi -> membrane
APC’s have special proteasome = “immunoproteasome” -> pieces are the correct length
- “transporter associated with processing” = TAP = channel into ER
Professional APC’s
Dendritic cells, B cells, macrophages
Express both MHC I and MHC II
Can provide co-stimulation to prime T cell response
MHC I structure
Peptide binding cleft part of variable alpha chain
- Alpha 1 and 2 = cleft, alpha 3 = stem
Invariable beta-2 microglobulin anchors
Assembled in ER, MHC recycled if antigen falls off
Usually binds ends of peptides (residues 1-2, 8-9)
MHC specificity
TCR binding region changes by individual
Peptide binding cleft - polymorphisms in pocket specific for anchor residues of peptide (determines binding affinity)
- diversity determined by recombination of HLA genes
MHC II pathway
Extracellular pathogens -> CD4
APC’s phagocytose in peripheral tissue (indiscriminate) -> endosome -> MHC II -> membrane -> CD4 T cell
Phagocytosis: dendritic cells and macrophages vs B cells
Dendritic cells, macrophages - resident in peripheral tissue
- indiscriminate - includes dead cells, etc
- only activated if pathogen -> migrate, costimulatory signal, etc
B cells - circulate
- specific antigen-depedent!
- can detect low concentrations -> present to CD4
(both BCR and TCR specific for same peptide - BCR is folded, TCR is small sequence + MHC II)
MHC II production
MHC unstable alone -> binds invariant chain in cleft -> cleaved to become CLIP
MHC in special vesicle joins endosome
Chaperone protein “DM” facilitates transfer of peptide into cleft (replaces CLIP)
Vesicle -> cell membrane
MHC II structure
Alpha and beta chain dimer
Binding pocket is alpha 1 + beta 1
Anchored by alpha 2 + beta 2
Binding region is flat -> wide range of binding sites and sizes (8-30 amino acids)
Cross-presentation of antigen
Necessary for mounting CD8 response against viruses that don’t infect APCs
Ex: flu -> lung epithelium -> APC takes in -> cross present to MHC I -> CD8 activated -> find and kill infected lung cells)
Mechanism = transport from endosome -> cytosol -> proteasome -> MHC I -> CD8
MHC genetics
HLA = human leukocyte antigen = human MHC
3 alleles each (A, B, C) x 2 chromosomes = 6 alleles for MHC I 3 alleles (DP, DQ, DR) -> 6 alleles for MHC II (plus even more variety bc dimerized) Determines range of peptides presented Co-dominance - all are expressed
Anatomy of APCs
Spleen - filters for bloodborne -> local APCs -> local T’s
Peripheral - immature dendritic cells circulate and phagocytose ->
encounter “pathogen associated molecular patterns” (PAMPs) ->
activated ->
migrate to lymph nodes, upregulate MHC’s, costimulatory molecules
