Immunology Fall 2026: Lecture 16 MHC Structure and Function

Overview

Brianne Barker explains how human HLA and mouse H-2 genetics relate to the structures and functions of MHC class I and class II. The lecture connects class I's closed peptide-binding groove, 8 to 10 amino acid peptides, cytoplasmic sources, and CD8 T cells with class II's open groove, longer peptides from endocytic compartments, and CD4 T cells, while clarifying which cells express each class.

Key takeaways

Human MHC haplotypes are groups of HLA genes on a chromosome that are usually inherited together, so identifying them requires tracking which alleles share a parental chromosome.
Class I grooves have closed ends and typically bind 8 to 10 amino acid peptides using allele-specific R-group anchor residues; class II grooves are open-ended and bind longer peptides with fewer strict side-chain requirements.
MHC class I presents peptides from the cytoplasm, including viral proteins, to CD8-positive killer T cells, linking intracellular infection signals to infected-cell killing.
MHC class II presents peptides from endocytic compartments to CD4-positive helper T cells, with B cells, dendritic cells, and macrophages serving as the three main professional antigen-presenting cell types.
Nearly all nucleated cells express MHC class I, while mature red blood cells do not; professional antigen-presenting cells express both class I and class II.
In common mouse strain nomenclature, Black 6 is H-2b, BALB/c is H-2d, and C3H is H-2k; an F1 offspring inherits one MHC chromosome from each parent.

Chapters

0:00 Human HLA Locus: Class I, Class II, and Class III Regions

The human MHC locus, called HLA, lies on the short arm of chromosome 6.
Class I genes are HLA-A, HLA-B, and HLA-C; class II genes are HLA-DP, HLA-DQ, and HLA-DR.
The class III region includes complement proteins and cytokines, while HLA-E, HLA-F, HLA-G, HLA-DM, and HLA-DO are related genes but not among the six classical class I and class II groups emphasized here.

4:55 MHC Haplotypes and Human HLA Allele Numbers

An MHC haplotype is a set of genes on one chromosome that is usually inherited together, with relatively little recombination across this long genomic region.
People inherit one MHC haplotype from each parent, and the genes on each chromosome remain grouped when identifying haplotypes.
HLA alleles are identified by numbers, such as HLA-A1 and HLA-A2; individuals generally express two versions each of HLA-A, HLA-B, and HLA-C.

8:36 Mouse Skin Grafts Reveal MHC Compatibility

Early mouse MHC genetics used skin grafts among inbred strains and their offspring to track transplantation compatibility.
A B-strain parent could accept grafts from B mice and B-by-K offspring, while a K-strain parent could accept grafts from K mice and those offspring.
The B-by-K progeny could accept grafts from other B-by-K progeny but not either parent, showing that graft acceptance depended on matching MHC alleles.
These inbred-mouse results should not be generalized to human transplantation, because humans are an outbred species.

13:54 Human HLA and Mouse H-2 Gene Systems

The mouse MHC locus is called H-2 and is located on chromosome 17; the human equivalent is the HLA locus on chromosome 6.
Mouse class I genes include H-2K, H-2D, and H-2L, while class II genes include H-2I-A and H-2I-E.
As a naming cue, HLA indicates human MHC and H-2 indicates mouse MHC; one-letter and two-letter gene names distinguish class I from class II in these examples.

16:07 Mouse Strain Alleles and H-2 Haplotypes

Unlike numbered human HLA alleles, mouse alleles use letter subscripts associated with familiar laboratory strains.
Black 6 mice are H-2b and BALB/c mice are H-2d, so the haplotype shorthand indicates the corresponding allele across the MHC region.
The C3H strain is H-2k; writing H-2k summarizes the strain's MHC alleles without listing each gene separately.

21:39 F1 Mouse Crosses and Outbred MHC Variation

An F1 mouse from C3H and BALB/c parents inherits one H-2k chromosome and one H-2d chromosome.
A wild outbred mouse cannot be summarized with a single inbred-strain haplotype, because its MHC alleles can be a mix of versions inherited from genetically distinct parents.
Laboratory strain reference charts help identify the MHC alleles used in common experiments, including BALB/c and Black 6 mice.

26:39 Protein Backbones, Amino Acids, and R-Group Shape

Proteins are chains of amino acids joined through their amino and carboxyl termini, forming a repeating N-C-C backbone, also called the main chain.
Each amino acid's R group differs in shape and charge; lysine has a long, charged side chain, while phenylalanine has a bulky hydrophobic side chain.
MHC peptide binding depends on molecular fit, so amino-acid side-chain shape and charge help explain why different MHC molecules bind different peptides.

33:00 MHC Class I Structure and Beta-2 Microglobulin

MHC class I has a variable heavy chain with alpha-1, alpha-2, and alpha-3 domains, a transmembrane region, and the noncovalently associated beta-2 microglobulin protein.
The alpha-1 and alpha-2 domains form the peptide-binding cleft, with two alpha helices above a beta-sheet platform.
Beta-2 microglobulin is encoded outside the MHC locus and is largely conserved; the variable peptide-binding region resides in the heavy chain.

38:29 Class I Peptide Length, Anchor Residues, and Binding Pockets

Class I peptide-binding clefts have closed ends, restricting typical peptides to 8 to 10 amino acids.
MHC class I pockets bind particular peptide R groups, called anchor residues, which stabilize a peptide in the cleft.
Peptide sequencing revealed allele-specific patterns, such as one class I type favoring glycine at position 2, proline at position 3, and leucine or isoleucine at position 9.
Other peptide residues remain exposed toward the T cell receptor, allowing one MHC allele to present multiple peptide epitopes.

45:21 Class I Presents Cytoplasmic Peptides for Infected-Cell Detection

MHC class I acquires peptides from proteins in the cytoplasm; viral proteins are a key example of this source.
Displaying a pathogen-derived peptide signals that a cell may be infected, making elimination of that cell an appropriate immune response.
Class I presentation connects to killer T cells, which recognize peptide-MHC complexes and can destroy infected cells.

50:51 CD8 Stabilizes Class I Recognition on Nucleated Cells

T cell receptors bind MHC-peptide complexes relatively weakly, so the CD8 coreceptor helps stabilize interactions with MHC class I.
CD8 binds a conserved region near the class I alpha-3 domain, allowing it to support recognition across different class I alleles.
Nearly every nucleated cell displays MHC class I; red blood cells are the exception because mature erythrocytes lack nuclei.
Each nucleated cell can display the six inherited class I versions: two each of HLA-A, HLA-B, and HLA-C.

56:48 MHC Class II Chains, Folding, and Molecular Stability

MHC class II consists of variable alpha and beta chains of similar size, each with an immunoglobulin domain and a transmembrane region.
The alpha-1 and beta-1 domains combine to form the peptide-binding cleft, unlike class I, whose cleft comes from one heavy chain.
Correct folding requires the class II alpha chain, beta chain, and peptide together; once assembled, the complex is exceptionally stable, even under SDS treatment.

1:01:11 Class II Peptide Binding and Endocytic Antigen Sources

Class II has an open-ended peptide-binding cleft, so peptide termini can extend beyond the groove and peptide length is less restricted than in class I.
Class II peptides often span about 14 to 20 amino acids, but longer peptides can bind because the groove ends are open.
Class II primarily interacts with peptide backbone atoms rather than specific R groups, so it does not have the same strict, position-specific anchor residues as class I.
Class II acquires peptides from endocytic compartments containing material taken up through endocytosis or phagocytosis.

1:06:52 CD4, Professional Antigen-Presenting Cells, and Haplotype Practice

MHC class II engages CD4-positive helper T cells; the pairing mnemonic is CD8 with class I and CD4 with class II.
The three professional antigen-presenting cell types are B cells, dendritic cells, and macrophages; they express both MHC class I and class II.
Most other nucleated cells express class I but not class II; thymic epithelial cells are a notable additional class II-presenting cell involved in T cell development.
Haplotype exercises require tracking which parental HLA-A, HLA-B, and HLA-DR alleles a child inherited together on each chromosome.

Transcript excerpt

0:00 Hi everybody. Hope that you are doing well. Um and I hope that you had a relaxing break. And perhaps even were not as completely useless as I was. Um So, grading still ongoing cuz I was useless. Um I will get information to you shoot. Um remember the flow cytometry problem set um today by 5:00 and you're welcome to come by um with whatever questions you might have. Um I'll also point out at the end of next week, so next Friday, so week and a half from now, there's an MHC problem set. Um it's posted already.

0:49 And like half of it you're going to be able to do after today's class. So, just FYI, that's there if you're you know, bored. Um But today I want to uh talk uh specifically about MHC structure and function. Um and sort of keep up in thinking about MHC after we did last time. Um So, we learned last time that the MHC genes are the most polymorphic genes in the human genome. Um And so these as I said, the number of different um alleles of the MHC genes are sort of the uh largest number of alleles of any gene in the human genome.

1:36 Um and today we need to talk a little bit more about um MHC genetics. Um in thinking about um some details of related to MHC. Um and so this is the um human uh MHC locus, um which is also as I told you last time, called the HLA locus. Um HLA standing for human MHC. Um this is the short arm of chromosome 6. And you can see that there are three regions, the class one region, the class two region, and the class three region. Um the class one region um contains the

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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.