How is the TCR structurally similar to an antibody?
Both have 2 chains, variable regions (antigen-binding site), constant regions, and membrane attachment. The TCR has α and β chains.
What does the TCR recognize, and which regions are involved?
The TCR recognizes antigenic peptides displayed on MHC molecules. The variable regions (Vα and Vβ) contact both the MHC and the peptide.
Why is the TCR–MHC–peptide interaction important beyond antigen recognition?
It’s also critical during T cell development in the thymus for positive and negative selection.
What are the structural similarities and differences between MHC I and MHC II?
Both have a peptide-binding cleft and similar domains. MHC I = 1 chain + β2-microglobulin. MHC II = 2 chains (α + β).
MHC I vs. MHC II: what antigen type does each present, and to which T cell?
MHC I → intracellular antigens → cytotoxic T cells (CD8+). MHC II → exogenous antigens → helper T cells (CD4+).
How do the peptides differ between MHC I and MHC II binding clefts?
MHC I: closed cleft → short contained peptides (8–10 aa). MHC II: open cleft → longer peptides that stick out at the ends.
What do CD4 and CD8 bind, and is the peptide involved?
CD4 binds MHC II; CD8 binds MHC I. The peptide is NOT involved in co-receptor binding. CD4/CD8 have low variability.
What are anchor residues and how do they differ between MHC I and II?
Anchor residues are conserved positions that allow peptide binding. MHC I: anchors at similar positions + C/N termini are key. MHC II: anchors are similar but at different locations (open cleft = more flexibility).
Why isn’t MHC expressed equally on all cell types?
Expression is linked to cell function. DCs/B cells express lots of MHC II for antigen presentation. Brain has little MHC (avoids strong T cell responses). Red blood cells have none.
Briefly outline the MHC I antigen processing pathway (intracellular).
- Intracellular proteins degraded by proteasome in cytosol. 2. Peptides transported into ER by TAP. 3. Peptide loaded onto MHC I with help of chaperones. 4. MHC I–peptide complex transported to cell surface.
What is the immunoproteasome and why does it matter?
Upon interferon exposure, proteasome subunits are replaced to form the immunoproteasome. It generates peptides that bind better to MHC I and are better transported by TAP. Subunits LMP2/LMP7 are encoded in the MHC locus.
Why does peptide size matter for MHC I, and how is the right size achieved?
MHC I has a closed cleft requiring 8–10 aa. The proteasome often makes peptides too long/short → TPPII aminopeptidase trims → TRiC chaperone stabilizes → ERAPs do final trimming in the ER.
What is TAP and what does it do?
TAP (Transporter Associated with Antigen Processing) is a heterodimer (TAP1/TAP2) that actively transports peptides (8–16 aa, hydrophobic/basic C-terminus) from cytosol into the ER. Encoded in the MHC locus.
What chaperones help load peptides onto MHC I in the ER?
Calnexin (early folding), then calreticulin, ERp57, tapasin (peptide loading complex). ERAAP does final trimming in the ER. MHC I is unstable until loaded with the right peptide.
Where are MHC II peptides generated, and in which cells does this happen?
In acidic endocytic compartments. Only in APCs of lymphoid origin (B cells, dendritic cells, macrophages, thymic epithelium).
What is the invariant chain (Ii) and what are its two jobs?
Ii is a trimer that: 1) blocks the MHC II cleft in the ER (prevents wrong peptides from binding) and 2) directs MHC II to acidic endosomes. It gets cleaved down to CLIP.
How does CLIP get removed from MHC II so the real antigen peptide can bind?
Cathepsins cleave Ii down to CLIP. Then HLA-DM (human) / H2-M (mouse) binds MHC II, releases CLIP, and allows actual antigen peptides to load.
What are the human and mouse names for the MHC, and what antigen-processing genes are encoded there?
Human: HLA. Mouse: H-2. Both encode TAP1/TAP2, LMP2/LMP7 (proteasome subunits), and HLA-DM/H2-M.
What is MARCH-1 and how does DC activation change its role?
MARCH-1 is an E3 ubiquitin ligase that degrades MHC II in immature DCs (keeps levels low). Upon activation, MARCH-1 transcription stops → MHC II accumulates at the surface → better antigen presentation to T cells.
What is cross-presentation and why is it important?
Cross-presentation = DCs present exogenous antigens via MHC I. Mechanism: ingested proteins escape phagolysosome → cytosol → proteasome → ER → MHC I. Critical for priming CD8 T cells against tumors/viruses that block normal MHC I presentation.
How can cellular antigens be presented by MHC II? (other form of cross-presentation)
Via autophagy: cytoplasmic contents are engulfed by autophagosomes → fuse with endosomes → peptides loaded onto MHC II.
Give 3 general strategies viruses use to evade MHC I presentation.
- Prevent proteasomal degradation (e.g. EBV EBNA1 resists degradation). 2. Block TAP transport (e.g. HSV ICP47). 3. Target MHC I for degradation (e.g. HCMV US2/US11).
Why is cross-presentation especially important in the context of viral immune evasion?
If a virus blocks MHC I presentation in infected cells, DCs can still cross-present viral antigens to activate CD8 T cells and eliminate the infection.
Why is HCMV a good model for studying immune evasion?
HCMV has many immune evasion genes targeting virtually every step of MHC I presentation. Studying them revealed fundamental cell biology (e.g., ERAD — protein transport from ER to cytosol for degradation).
