Immunology Fall 2026: Lecture 18 Antigen Presentation by MHC Part 2
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Overview
Brianne Barker compares MHC class I presentation with MHC class II processing, explaining how phagocytosis or B-cell receptor-mediated endocytosis supplies antigens, invariant chain and CLIP control peptide loading, and HLA-DM enables peptide exchange. She then connects presentation to dendritic-cell cross-presentation, CD1 lipid recognition by NKT cells, and viral strategies that interfere with MHC class I, which helps explain why natural killer cells detect cells missing MHC I.
Key takeaways
- MHC class II presentation depends on active antigen acquisition: macrophages and dendritic cells phagocytose large material, while B cells internalize antigen bound to their B-cell receptors.
- Invariant chain protects the MHC class II cleft and directs trafficking; its remaining fragment, CLIP, is removed through HLA-DM-mediated peptide exchange.
- Dendritic-cell cross-presentation allows antigens acquired from infected cells to enter the MHC class I pathway, enabling CD8 T-cell priming even when the pathogen does not infect dendritic cells.
- CD1 molecules present lipids to NKT cells, using an MHC class I-like structure with hydrophobic pockets and an endocytic processing route.
- Viral interference with proteasomes, TAP, tapasin, or surface MHC class I can block antigen presentation, but loss of MHC I also exposes infected cells to natural killer cells.
- MHC class I escape mutations are constrained by human MHC diversity: a mutation that evades CD8 T cells in one person may fail to evade recognition in another.
Chapters
- The antigen-presentation discussion paper is canceled, and the updated schedule lists an MHC problem set for Friday.
- Brianne Barker plans to return graded exams after class and post grades and answer keys on Moodle.
- The lecture focuses on MHC class II, building on the six-step MHC class I presentation pathway from the previous class.
- MHC class II consists of alpha and beta chains that form a peptide-binding cleft; peptide-bound complexes are highly stable.
- MHC class II presents peptides to CD4-positive T cells, with CD4 helping stabilize the interaction.
- The main professional MHC class II antigen-presenting cells are dendritic cells, macrophages, and B cells.
- Unlike MHC class I, which draws peptides from the cytoplasm, MHC class II receives peptides from the endocytic or endomembrane pathway.
- Macrophages and dendritic cells can engulf large microbes through phagocytosis, an active process involving substantial cytoskeletal remodeling.
- Phagocytosis creates a phagosome, which can mature and fuse with lysosomes to degrade its contents.
- Macrophages, dendritic cells, and neutrophils are the three cell types identified as capable of phagocytosis.
- Unlike macrophages and dendritic cells, B cells acquire antigen through endocytosis rather than phagocytosis.
- When an antigen binds the B-cell receptor, the cell internalizes the receptor-antigen complex into an endosome.
- The B-cell receptor separates from the antigen and recycles to the cell surface, while the antigen remains in the endosome for processing.
- For MHC class II, entering a phagosome or endosome effectively marks an antigen for destruction; unlike MHC class I, ubiquitin tagging is not required.
- Endosomes mature, acidify, and interact with lysosomes, the degradative organelles for material outside the cytoplasm.
- Lysosomes contain acid-activated enzymes that break down biomolecules, while their low pH helps limit enzyme activity if enzymes escape into the neutral cytoplasm.
- MHC class II and endosomal peptides share the vesicular system, but class II could bind unintended peptides in the ER before reaching its intended loading compartment.
- A peptide-bound MHC class II molecule is highly stable, making it difficult to displace an early, incorrect peptide.
- Invariant chain, abbreviated Ii, blocks the class II peptide-binding cleft and provides a trafficking signal that directs the complex toward endosomal compartments.
- As MHC class II moves through increasingly acidic compartments, enzymes progressively digest invariant chain.
- The invariant-chain fragment left in the peptide-binding cleft is called CLIP, short for class II-associated invariant-chain peptide.
- CLIP keeps the cleft occupied until MHC class II reaches the compartment where antigen-derived peptides are available.
- Human HLA-DM, called H2-M in mice, promotes CLIP release from MHC class II so antigen-derived peptides can bind.
- HLA-DM repeatedly facilitates peptide exchange until a peptide binds strongly enough to resist displacement.
- This peptide-editing process acts as quality control, favoring stable peptide-MHC class II complexes.
- MHC class II surface display is active and regulated, unlike the more passive MHC class I display described in class.
- After activation, dendritic cells move MHC class II-containing vesicles along microtubules toward the cell surface.
- The surface increase helps a dendritic cell present peptide-MHC complexes to an interacting T cell.
- Dendritic cells are especially effective at activating naive T cells because they express additional proteins that support T-cell activation.
- A virus restricted to liver cells may be presented on MHC class I by infected liver cells, which are relatively poor at initiating a strong naive CD8 T-cell response.
- If a pathogen does not infect dendritic cells, dendritic cells can still acquire material from infected cells and present it through cross-presentation.
- Dendritic cells can phagocytose a virus-infected or dead liver cell and route acquired viral proteins into the MHC class I pathway.
- Cross-presentation lets dendritic cells activate CD8 T cells against pathogens that do not infect the dendritic cells themselves.
- The precise routes by which antigens move between cytoplasm, ER, and endosomal compartments remain incompletely understood.
- CD1 molecules present lipids rather than peptides; their overall structure resembles MHC class I, including a heavy chain and beta-2 microglobulin.
- CD1 has deep hydrophobic pockets that accommodate lipid tails, with a more exposed region for the lipid head group.
- CD1 lipid acquisition uses an endocytic processing route resembling MHC class II processing, and CD1 is important for responses to lipid-rich mycobacteria such as Mycobacterium tuberculosis.
- CD1 presents to NKT cells, a distinct T-cell population, rather than conventional CD4 or CD8 T cells; humans have several CD1 types, while mice have fewer.
- A mutation that prevents a viral peptide from binding one person's MHC class I can impair recognition by that person's CD8 T cells.
- Because people have different MHC molecules, an escape mutation useful in one host may not help the virus in the next host.
- Barker notes that this kind of peptide-specific escape is uncommon, with greater opportunity in long-lasting infections or transmission between people with shared MHC.
- Epstein-Barr virus protein EBNA1 contains a glycine-alanine-rich sequence that resists proteasomal degradation, preventing EBNA1 peptides from reaching MHC class I.
- Human cytomegalovirus and herpes simplex virus produce proteins that block TAP, limiting peptide transport from cytoplasm to ER and reducing presentation of both viral and self peptides.
- Adenovirus E19 disrupts the interaction between MHC class I and tapasin, impairing peptide loading; other viruses can remove MHC class I from the cell surface.
- Healthy cells continuously display self peptides on MHC class I, so loss of MHC I can signal that a virus has disrupted antigen presentation.
- Natural killer cells respond to this missing-self signal and can kill cells that lack surface MHC class I.
- Missing MHC class II is not used in the same way because MHC class II is normally limited to certain cell types and can vary with activation.
Transcript excerpt
0:00 All right. Um, I hope that you all had a great weekend um, and that everybody is doing well. Um, couple of general announcement types of things before I get started. Um, so some of you guys um, emailed me about what was going on with the discussion paper or upcoming assignments and things. Um, and I posted an updated schedule uh, this morning. So, you can find an updated schedule this morning. The antigen presentation um, discussion paper is not happening. Um, so I've taken that one off. Um, and I've moved around a couple of the other discussion papers. I have not yet changed the Moodle deadline the Moodle dates, but I will.
0:48 Don't worry. It'll be okay. Um, so you can see that that information that on the schedule is now up-to-date. Um, specifically the things I'll just point out are remember that there is an MHC antigen presentation problem set um, on Friday of this week. Um, and you'll also can see that there's a primary assignment on Monday next week um, which I will um, get you some more information about later today. Um, so that's the story there. Um, I have your graded exams. Um, which I will give back at the end today. No, I didn't put the grades on Moodle cuz then I figured you'd just stare at them instead of listening to what I was
1:34 saying. >> [laughter] >> Um, so I'll put that up on Moodle um, after class um, and um, answer keys for all of the problem sets you've done so far are posted. I need to do the exam answer key and I need to finish putting the the other stuff up on Moodle. So, it's coming, but I'm getting there. I am making progress. Um so today we're going to talk about
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Related notes
Summary, takeaways, and chapters were generated by AI from the video's transcript and may contain errors. The video belongs to its creator, Brianne Barker.