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USMLE Step 1ImmunologyEP 01 of 14

MHC I vs MHC II: how antigen presentation works

MHC I vs MHC II comes down to one rule: class I shows what the cell made inside, class II shows what the cell swallowed from outside. Each class has its own machinery and its own T cell.

  • 5:03 video
  • 3 min read
  • 4 sources
  • Published 15 Nov 2026
Video lesson · 5:03 · Watch on YouTubeSeries: Immunology · @medservatory
Chapters (10)
By the end of this lesson

Contrast the MHC class I (endogenous: proteasome, TAP, endoplasmic reticulum) and MHC class II (exogenous: endosome, invariant chain, CLIP, HLA-DM) antigen processing pathways, and name the T-cell subsets that recognise each (CD8 with class I; CD4 with class II).

The short version

  1. A conventional T cell reads a short peptide held in the groove of an MHC molecule (HLA in humans) on another cell, never a whole protein.
  2. Class I shows inside peptides to CD8 T cells; class II shows outside peptides to CD4 T cells.
  3. Class I needs the proteasome and TAP; class II needs the invariant chain, CLIP and HLA-DM.
  4. CD8 grips the alpha-3 domain of class I; CD4 grips the beta-2 domain of class II.
  5. Exception: dendritic cells can load swallowed antigen onto class I, which is cross-presentation.

What a T cell reads: a peptide in the MHC groove

Picture a liver cell infected with a virus. One viral fragment, about nine amino acids long, appears on its surface, and a passing T cell reads it and kills the cell. But that fragment was made inside the cytoplasm, so how does it reach the outside? The answer is the difference between MHC I vs MHC II antigen presentation.

A T cell cannot read a whole protein. It reads a short peptide held in the groove of an MHC molecule on another cell. In humans, MHC molecules are called HLA.[2][3]

MHC I vs MHC II: where they sit and how they are built

Class I sits on every nucleated cell. Class II sits mainly on professional antigen-presenting cells: dendritic cells, macrophages and B cells.[1][3]

Class I is a long alpha chain plus a small partner, beta-2 microglobulin. Class II is an alpha chain and a beta chain of similar length.[1][3]

MHC class I compared with MHC class II
FeatureMHC class IMHC class II
Where it sitsEvery nucleated cellMainly professional antigen-presenting cells (dendritic cells, macrophages, B cells)
ChainsLong alpha chain plus beta-2 microglobulinAlpha chain and beta chain of similar length
Peptide sourceMade inside the cellSwallowed from outside the cell
Co-receptorCD8 (alpha-3 domain)CD4 (beta-2 domain)
T cell that reads itCD8 cytotoxic T cellCD4 helper T cell

The MHC class I pathway: proteasome, TAP and the endoplasmic reticulum

Class I is the inside route. A viral protein in the cytoplasm is chopped by the proteasome into short peptides, which end up about nine amino acids long.[3][4]

But class I is built inside the endoplasmic reticulum, on the other side of a membrane. So a pump, TAP, the transporter associated with antigen processing, carries the peptides into the endoplasmic reticulum.[3]

  1. ProteasomeCytoplasmic protein is cut into short peptides.
  2. TAPThe pump carries the peptides into the endoplasmic reticulum.
  3. LoadingThe peptide is loaded onto class I with its beta-2 microglobulin partner.
  4. SurfaceThe complex travels to the cell surface.
  5. ReadingA CD8 cytotoxic T cell reads it and, if the peptide is viral, kills the cell.[1][2]

The MHC class II pathway: invariant chain, CLIP and HLA-DM

Class II is the outside route. A dendritic cell swallows a bacterium into a phagosome, which fuses with a lysosome, and enzymes cut the protein into peptides.[1][3]

Meanwhile class II is built in the endoplasmic reticulum with a plug in its groove, the invariant chain, so it cannot pick up the cell's own peptides there by mistake. In the late endosome, where it meets the swallowed protein's peptides, the plug is trimmed to a small stub called CLIP, and HLA-DM swaps CLIP for one of those peptides.[3]

  1. PhagolysosomeThe swallowed protein is cut into peptides.
  2. Invariant chainA plug keeps the groove closed while class II is built.
  3. CLIPThe plug is trimmed to a small stub.
  4. HLA-DMIt swaps CLIP for a peptide from the swallowed protein.
  5. ReadingThe complex reaches the surface and a CD4 helper T cell reads it.[1][2]

CD8 and CD4: the co-receptor decides the class

CD8 grips the alpha-3 domain of class I. CD4 grips the beta-2 domain of class II. This is why CD8 cells read class I and CD4 cells read class II.[2][3][4]

Memory trick
CD8 × MHC I = 8; CD4 × MHC II = 8

8 × 1 = 8 and 4 × 2 = 8; a teaching aid, not a biological rule

The exception: cross-presentation

Dendritic cells can load swallowed antigen onto class I. That is cross-presentation.[1][3]

Practice question

Original · USMLE style
Your turnQB-MS-S1-IMM-005-01

A 7-year-old boy has had chronic purulent rhinitis, and sinus and ear infections, since early childhood. Flow cytometry of his peripheral blood lymphocytes shows markedly reduced surface HLA class I expression, with normal HLA class II expression.

Which of the following steps is most likely impaired?
Pick one option. Your answers stay on this device.

Common questions

What is the difference between MHC class I and MHC class II?

Class I sits on every nucleated cell and shows peptides made inside the cell to CD8 T cells. Class II sits mainly on professional antigen-presenting cells and shows peptides swallowed from outside to CD4 T cells.

What does TAP do in antigen presentation?

TAP, the transporter associated with antigen processing, is a pump that carries peptides made by the proteasome into the endoplasmic reticulum, where class I is built.

What are the invariant chain, CLIP and HLA-DM?

The invariant chain is a plug in the class II groove that stops the cell's own peptides in the endoplasmic reticulum from binding. It is trimmed to a stub called CLIP, and HLA-DM swaps CLIP for a peptide from the swallowed protein.

Which T cell binds MHC I and which binds MHC II?

CD8 cytotoxic T cells bind class I, gripping its alpha-3 domain. CD4 helper T cells bind class II, gripping its beta-2 domain.

What is cross-presentation?

Cross-presentation is when dendritic cells load swallowed antigen onto class I, so that it is shown to CD8 T cells.

Transcript

Read the full narration, by chapter647 words

0:00The puzzle: a peptide made inside, shown outside

Picture a liver cell infected with a virus. One viral fragment, about nine amino acids long, appears on its surface, and a passing T cell reads it and kills the cell. But that fragment was made inside the cytoplasm. How does it reach the outside? Today: compare the two antigen presentation pathways, MHC I and MHC II, and the T cells that read them.

0:26A T cell reads a peptide in the MHC groove (HLA)

AT cell cannot read a whole protein. It reads a short peptide held in the groove of an MHC molecule, called HLA in humans, on another cell.

0:37Where class I and class II sit

Class I sits on every nucleated cell. Class II sits mainly on professional antigen-presenting cells: dendritic cells, macrophages and B cells.

0:49The chains of each class, and the rule: inside vs outside

Class I is a long alpha chain plus a small partner, beta-2 microglobulin. Class II is an alpha chain and a beta chain of similar length. The rule: class I shows what the cell made inside; class II shows what the cell swallowed from outside.

1:08Class I: proteasome, TAP, loading, CD8 T cell

First, class I, the inside route. A viral protein in the cytoplasm is chopped by the proteasome into short peptides, which end up about nine amino acids long. But class I is built inside the endoplasmic reticulum, on the other side of a membrane. So a pump, TAP, the transporter associated with antigen processing, carries the peptides into the endoplasmic reticulum. There the peptide is loaded onto class I with its beta-2 microglobulin partner, and the complex travels to the surface. A CD8 cytotoxic T cell reads it, and if the peptide is viral, kills the cell.

1:51Class II: phagosome, invariant chain, CLIP, HLA-DM, CD4 T cell

Now class II, the outside route. A dendritic cell swallows a bacterium into a phagosome, which fuses with a lysosome, and enzymes cut the protein into peptides. Meanwhile class II is built in the endoplasmic reticulum with a plug in its groove, the invariant chain, so it cannot pick up cytoplasmic peptides by mistake. The plug is trimmed to a small stub called CLIP, and HLADM swaps CLIP for a peptide from the swallowed protein. The complex reaches the surface, and a CD4 helper T cell reads it.

2:28The co-receptor decides the class (CD8 and alpha 3, CD4 and beta 2); the exception: cross-presentation

The co-receptor decides the class. CD8 grips the alpha-3 domain of class I. CD4 grips the beta-2 domain of class II. A memory trick: CD8 times MHC I is 8, and CD4 times MHC II is also 8. One exception: dendritic cells can load swallowed antigen onto class I. That is cross-presentation.

2:56Practice question

Your turn. A 7-year-old boy has had chronic purulent rhinitis, and sinus and ear infections, since early childhood. Flow cytometry of his lymphocytes shows markedly reduced surface HLA class I, with normal HLA class II. Which of the following steps is most likely impaired? A, cleavage of the invariant chain in endosomes. B, transcription of the genes encoding MHC class II. C, transport of peptides into the endoplasmic reticulum. D, binding of CD4 to the beta-2 domain of MHC class II. E, binding of CD8 to the alpha-3 domain of MHC class I. Pause here and decide.

3:47Answer and explanation (type I bare lymphocyte syndrome)

A is out: the invariant chain belongs to the class II route, and his class II is normal. B is out: that would lower class II, not class I. D is out: CD4 binding is a class II step, not a class I loading step. E is out: CD8 binding affects recognition, not how much class I reaches the surface. So the answer is C. Without TAP, peptides cannot enter the endoplasmic reticulum, class I cannot be loaded, and little reaches the surface; this is type I bare lymphocyte syndrome.

4:26Recap and next lesson

Three things to keep. One: class I shows inside peptides to CD eight cells; class II shows outside peptides to CD4 cells. Two: class I needs the proteasome and TAP; class II needs the invariant chain, CLIP and HLADM. Three: CD8 grips alpha-3 of class one; CD4 grips beta-2 of class II. Next, what else a T cell needs to switch on: the two signal model.

Sources

Numbers in the text, e.g. [1], point here
  1. OpenStax Microbiology 18.2: Major Histocompatibility Complexes and Antigen-Presenting Cells. openstax.org/books/microbiology/pages/18-2-major-histocompatibility-complexes-and-antigen-presenting-cells
  2. OpenStax Microbiology 18.3: T Lymphocytes and Cellular Immunity. openstax.org/books/microbiology/pages/18-3-t-lymphocytes-and-cellular-immunity
  3. Europe PMC open-access reviews (antigen processing, TAP deficiency, CIITA, cross-presentation): europepmc.org/article/PMC/PMC5355494 · europepmc.org/article/PMC/PMC6394470 · europepmc.org/article/PMC/PMC6054923 · europepmc.org/article/PMC/PMC11381289 · europepmc.org/article/PMC/PMC13107469 · europepmc.org/article/PMC/PMC12537883 · europepmc.org/article/PMC/PMC13177779 · europepmc.org/article/PMC/PMC12829761
  4. Background: en.wikipedia.org/wiki/Antigen_processing · en.wikipedia.org/wiki/CD8 · en.wikipedia.org/wiki/CD4

The cells and molecules on screen are schematic and not to scale. Peptides are usually 8 to 10 amino acids long; the lesson uses about nine.

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): hepatitis virus, sinusitis, Golgi apparatus. NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain: hepatocyte, MHC class I, dendritic cell, macrophage, lysosome, T cell. Icons via bioicons.com, adapted: MHC I and MHC II (Helicase 11, CC BY 4.0, labels removed), B cell (El-Jayawant, CC BY 4.0), endoplasmic reticulum (jaiganesh, CC0). The peptides, proteasome, TAP pump, bacterium, plug, CLIP, HLA-DM, histograms, cards and all handwriting are drawn in code (original). No AI-generated teaching images.

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-IMM-005.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
  1. EP 01MHC I vs MHC II: how antigen presentation works5:03
  2. EP 02T-cell activation: the two-signal model4:58
  3. EP 03Th1, Th2, Th17 and Treg: helper T-cell subsets5:13
  4. EP 04Antibody isotypes and class switching5:13
  5. EP 05Central vs peripheral tolerance: how lymphocytes learn self-tolerance5:26
  6. EP 06Complement system explained: three pathways, one ending5:24
  7. EP 07Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor5:15
  8. EP 08Hypersensitivity types I to IV: the four effectors5:20
  9. EP 09B-cell vs T-cell immunodeficiency: predict the infections5:24
  10. EP 10Hyper IgM syndrome: CD40 ligand and class switching5:19
  11. EP 11Chronic granulomatous disease: NADPH oxidase and the respiratory burst5:20
  12. EP 12Leukocyte adhesion deficiency: CD18 and neutrophil extravasation5:01
  13. EP 13Transplant rejection explained: hyperacute, acute, chronic and GVHD5:51
  14. EP 14Vaccine types explained: live, inactivated, conjugate and mRNA5:41