Immunology Fall 2026: Lecture 15 T cells and MHC
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Overview
Brianne Barker explains how T cells address gaps left by phagocytosis and antibodies, especially infection hidden inside cells, and how T cell receptors recognize pathogen-derived peptides displayed by MHC. She connects the 1996 Nobel Prize-winning Zinkernagel and Doherty experiment, chromium-release assays, and HLA genetics to explain MHC restriction, peptide-binding diversity, and why immune responses differ among people and species.
Key takeaways
- CD8 T cells address the intracellular infection gap by killing infected cells, a threat antibodies generally cannot reach while pathogens replicate inside host cells.
- Zinkernagel and Doherty's LCMV experiments showed that CD8 T cells killed targets only when both the viral antigen and the host MHC matched, establishing MHC restriction.
- MHC molecules display short peptides from intracellular proteins, and T cell receptors contact both the peptide and the presenting MHC molecule.
- Human HLA genes are highly polymorphic, and differences in their peptide-binding pockets make each person's T cell response to a pathogen partly unique.
- HLA diversity can help protect populations from shared infectious threats, while low MHC diversity can leave species such as Tasmanian devils vulnerable to transmissible tumors.
- An HLA type can have contrasting effects: HLA-B*27 is associated with better control of HIV but also with autoimmune diseases such as ankylosing spondylitis.
Chapters
- Barker frames T cells as the next topic after B cells, whose development and antibody responses can require T cell help.
- The lecture begins by identifying gaps in previously covered immune mechanisms, especially threats hidden inside cells.
- T cell antigen recognition receives extended attention because it involves MHC presentation.
- Some microbes, including Salmonella and Mycobacterium tuberculosis, alter phagosomes and survive inside phagocytes.
- Listeria monocytogenes can escape the phagosome, making ordinary intracellular degradation insufficient.
- Antibodies bind exposed pathogen surfaces, so internal viral components are inaccessible and changing surface proteins can evade recognition.
- Antibodies mainly act outside cells, leaving intracellular stages of viral replication beyond their direct reach.
- T cells are a heterogeneous lymphocyte group, unlike the simplified description of B cells as antibody producers.
- CD8 T cells kill infected target cells, while CD4 T cells release cytokines that alter other cells' behavior.
- CD4 helper activity can improve macrophage killing and support B cells in producing better antibodies.
- The typical T cell receptor has alpha and beta chains linked by a disulfide bond, with variable and constant immunoglobulin domains.
- Each chain contributes three complementarity-determining loops, giving the receptor a structure resembling an antibody Fab arm.
- Because T cells must detect what is inside cells, their receptor's antigen target raises the central question of how intracellular contents become visible.
- Rolf Zinkernagel and Peter Doherty used LCMV-infected mice in work that earned the 1996 Nobel Prize.
- Inbred strain A and strain B mice are genetically distinct from one another, but individuals within each strain are nearly genetically identical.
- The researchers isolated CD8 T cells from LCMV-infected strain A mice to test which target cells those T cells could kill.
- In the classic cytotoxicity assay, target cells are loaded with radioactive chromium; cell death releases chromium into the surrounding medium.
- Strain A CD8 T cells killed strain A cells infected with LCMV, but not uninfected cells or cells infected with influenza.
- The T cells also failed to kill LCMV-infected strain B cells, showing that recognition depends on both the pathogen and the host's MHC.
- This pattern established the principle of MHC restriction: a T cell responds to its target peptide when displayed by compatible self MHC.
- Proteins from inside a cell are broken into peptide fragments and displayed on MHC molecules at the cell surface.
- The T cell receptor recognizes both the presented peptide and the MHC molecule, so an incorrect peptide or incorrect MHC prevents activation.
- Unlike B cell receptors and antibodies, T cell receptors require MHC and recognize protein-derived peptides rather than carbohydrates, lipids, or nucleic acids.
- MHC also displays peptides from healthy cellular proteins, providing T cells with information about the cell's internal state.
- The MHC peptide-binding cleft holds a linear peptide fragment, with some amino acid side chains anchored in the cleft.
- Other peptide residues project upward and contact the T cell receptor, whose alpha- and beta-chain loops touch both peptide and MHC.
- The receptor approaches the MHC-peptide complex at a diagonal angle, contacting the MHC alpha helices around the binding groove.
- The human MHC, called HLA, occupies a large region on the short arm of chromosome 6.
- The HLA complex includes class I and class II regions, plus a class III region containing other immune genes such as complement and cytokine genes.
- Human class I genes include HLA-A, HLA-B, and HLA-C; class II genes include HLA-DP, HLA-DQ, and HLA-DR.
- HLA genes are codominantly expressed, so Barker describes products inherited from both parents appearing on cells.
- HLA genes are among the most polymorphic in the human genome, with the lecture citing about 2,980 HLA-A, 3,700 HLA-B, and 2,661 HLA-C variants.
- Most variation among MHC molecules affects the peptide-binding pocket, changing which peptide sequences can be presented.
- A person's inherited set of MHC molecules therefore displays a distinct selection of pathogen-derived peptides.
- Barker's chalk model represents protein fragments as short amino acid sequences whose shapes determine whether they fit particular MHC pockets.
- Each MHC molecule can present multiple peptides that share suitable anchor features, while different MHC molecules select different fragments.
- T cell receptors contact exposed peptide features, so people with different MHC types can build responses to different parts of the same pathogen.
- The example of H-2Kᵈ shows a binding preference for tyrosine at peptide position 2 and valine or isoleucine at position 9.
- Different HLA types can present different viral peptides, producing stronger or weaker T cell responses to the same infection.
- Barker uses HIV as an example: HLA-B*13:01 is associated with lower viral levels and slower progression, while some other HLA types are less protective.
- Codominant expression gives each person multiple MHC options, but a particular individual can still lack an especially effective presentation route.
- Population-wide HLA diversity increases the chance that some people can mount effective responses to a new pathogen.
- The lecture describes a sweaty T-shirt experiment in which college-age women reportedly favored the scent of men with more different MHC alleles.
- Geographic differences in HLA frequencies can inform investigations of disease outbreaks, vaccine needs, and population relationships.
- MHC matching can also contribute to identification and kinship analyses, including paternity testing.
- Many autoimmune diseases are associated with particular MHC types that can present relevant self peptides.
- HLA-B*27 illustrates the trade-off: it is associated with strong HIV control but also with ankylosing spondylitis and other autoimmune conditions.
- An MHC association can point researchers toward an immune mechanism, although not every associated disease is necessarily explained by immunity alone.
- Cheetahs have low MHC diversity, increasing concern that a pathogen could threaten much of the population.
- Tasmanian devils frequently bite one another and have limited MHC diversity, which can prevent them from rejecting transmissible facial tumors as foreign grafts.
- The lecture links transplant rejection to MHC differences and closes by contrasting human population diversity with species vulnerable to low MHC variation.
Transcript excerpt
0:00 All right. So, I am going to go ahead and get started. Um just a reminder. We talked about flow cytometry last time and you have the flow cytometry problems that do after break. Um on Wednesday, so definitely make sure that you take a look at that and you know, come by if you have questions. Let me know if you need help with parts of that. Um today we are going to start talking about T cells after our saga of B cells got on pause because we learned that the next step of the B cells life required it to interact with T cells. Um so now we got to think about T cells.
0:48 Um, one thing to note is: if you look back at some of the, um, antibody and B cell lectures, I, uh, first introduced you to, um, antibodies. And then I had like a little diversion of, I don't know, half a lecture or so about antigens and some of the specific details of antigens with B cells, and then we went back to sort of B cells, B cell development, all that kind of stuff. We're going to use that same kind of approach in thinking about T cells. Um the big difference is that with T cells um talking about the antigen doesn't take like half a lecture, it takes like three
1:35 lectures. Um but in the end it's actually the same general idea. It's just I'm going to be talking about the antigen for a bit longer. Um so today I'm going to start by introducing T cells and MHC and I will also say this particular lecture is one of my faves. Um so at this point you might say, "Okay, we're learning about a new mechanism of the immune
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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.