Major Histocompatibility Complex Molecules The Peptide Display System of Adaptive Immunity

Slide 1 · Major Histocompatibility

Complex Molecules

The peptide display system of adaptive immunity

MHC class I · CD8⁺

MHC class II · CD4⁺

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Relate HLA gene architecture and polymorphism to antigen display.

Distinguish class I and class II structure, distribution, and peptide sources.

Trace antigen processing to CD8⁺ and CD4⁺ T-cell recognition.

Explain HLA-dependent immune responses and transplantation compatibility.

Slide 3 · T cells recognize processed protein antigens

Protein antigen

Microbial, tumor, or other protein

Peptide fragment

Generated by proteolysis

MHC display

Peptide presented at cell surface

TCR recognition

Antigen-specific T lymphocyte

The T-cell receptor recognizes a peptide in the context of its displaying MHC molecule.

Slide 4 · Peptide display makes intracellular events visible

Inside a host cell

After cellular uptake

Microbial or abnormal proteins are processed

Ingested proteins are digested in vesicles

Peptides enter the class I presentation route

Peptides enter the class II presentation route

CD8⁺ cells survey the presented peptides

CD4⁺ cells respond to the presented peptides

Slide 5 · T cells and B cells recognize different antigen forms

Feature

T lymphocyte

B lymphocyte

Recognized target

Peptide–MHC complex

Native antigen via membrane Ig

Main receptor

T-cell receptor (TCR)

B-cell receptor (BCR)

Functional connection

Cell-mediated response or helper function

Antibody production after activation

Slide 6 · Why “major histocompatibility complex”?

MHC molecules were identified through their role in graft rejection.

Differences between individuals influence tissue compatibility.

In humans these molecules are called human leukocyte antigens (HLA).

They became central to understanding antigen recognition and immune disease.

Slide 7 · The HLA system is encoded on chromosome 6

Chromosome 6 · HLA gene complex

HLA-DP

HLA-DQ

HLA-DR

Other genes

HLA-B

HLA-C

HLA-A

Class II region

Class I region

Slide 8 · Two molecular classes divide peptide-display tasks

MHC class I

MHC class II

Displays peptides derived from cytosolic proteins

Displays peptides derived from internalized proteins

Recognized by CD8⁺ T cells

Recognized by CD4⁺ helper T cells

Supports elimination of infected or tumor cells

Supports macrophage activation and antibody responses

Slide 9 · HLA alleles are exceptionally polymorphic

Human populations contain thousands of HLA gene alleles.

Sequence variation changes the peptides that individual molecules can bind.

Most unrelated individuals express different HLA combinations.

This diversity contributes to immune breadth and graft incompatibility.

Slide 10 · The HLA locus contains distinct class I and II regions

Class I

HLA-A, HLA-B, and HLA-C encode class I heavy chains.

Class II

HLA-DP, HLA-DQ, and HLA-DR encode class II molecules.

Additional genes

The complex also includes genes for antigen-processing proteins.

Slide 11 · HLA-A, HLA-B, and HLA-C encode class I heavy chains

Three closely linked genes encode the polymorphic α chain of class I MHC.

Their protein products bind diverse peptides through variable groove residues.

Each expresses a form of class I molecular display at the cell surface.

Slide 12 · Class I display is broadly distributed

Nucleated host cell

CLASS I

Virus-infected cell

CLASS I

Potential tumor cell

CLASS I

Platelet

CLASS I

Broad host-cell surveillance for cytosolic antigens

Slide 13 · MHC class I consists of two associated proteins

α1

α2

Bound peptide

α3

β₂m

Schematic: Peptide groove formed by α1 and α2

Polymorphic α heavy chain

Nonpolymorphic β₂-microglobulin

α1 / α2 create groove

α3 contacts CD8

Slide 14 · Class I heavy chain contains three external domains

The heavy α chain has α1, α2, and α3 extracellular domains.

The α1 and α2 domains construct the peptide-binding cleft.

The α3 domain provides a contact site for the CD8 coreceptor.

The nonpolymorphic β₂-microglobulin associates noncovalently with the heavy chain.

Slide 15 · The class I peptide groove is formed by α1 and α2

α1

α2

Bound peptide

α3

β₂m

Schematic: Peptide groove formed by α1 and α2

Polymorphic α heavy chain

Nonpolymorphic β₂-microglobulin

α1 / α2 create groove

α3 contacts CD8

Slide 16 · Class I allele variation changes the peptide repertoire

Same antigen protein

Derived peptide

HLA variant A

HLA variant B

Peptide can bind

Peptide binding differs

Illustrates allele-dependent peptide presentation, not an absolute binding prediction

Slide 17 · Class I samples proteins originating in the cytosol

Cellular source

Cytosolic proteins are a major source of class I peptide antigens.

Infection

Viral proteins can enter this processing pathway.

Neoplasia

Abnormal tumor proteins can generate displayed peptides.

Slide 18 · Viral infection creates class I antigen targets

Infected host cell

Viral proteins in cytosol

Peptide production

Proteasomal degradation

Class I display

Viral peptide at cell surface

CD8⁺ recognition

Potential CTL-mediated clearance

The target is the infected cell displaying a viral peptide–MHC class I complex.

Slide 19 · Tumor proteins may enter the class I pathway

Tumor cell

Abnormal cytosolic proteins

Protein degradation

Peptide fragments generated

Surface class I

Tumor-derived peptide displayed

CTL surveillance

Recognition permits tumor-cell killing

Class I displays intracellular tumor-derived antigens to CD8⁺ cytotoxic T cells.

Slide 20 · Proteasomes generate cytosolic peptide fragments

Cytosolic protein

Endogenous protein antigen

Proteasome

Protein degradation

Peptide fragments

Substrates for class I loading

Class I antigen processing begins with degradation of cytosolic proteins.

Slide 21 · Class I peptides enter the endoplasmic reticulum

Cytosolic peptide

Product of proteasomal processing

Transport to ER

Peptides move into ER

New class I

Peptide binds developing molecule

Antigen processing and class I assembly converge within the endoplasmic reticulum.

Slide 22 · Peptide binding stabilizes the class I complex

Newly synthesized class I molecules bind suitable peptides in the ER.

Association with β₂-microglobulin supports a stable peptide–MHC complex.

The assembled complex is subsequently transported to the plasma membrane.

Slide 23 · Surface trafficking completes class I presentation

ER complex

Peptide-loaded MHC class I

Cell trafficking

Stable complex transported

Plasma membrane

Extracellular display

CD8⁺ survey

TCR scans peptide–MHC

A cytosolic antigen becomes accessible to lymphocytes outside the cell.

Slide 24 · Class I antigen processing: Integrated pathway

Cytosol

Protein source

Proteasome

Peptide generation

ER

Peptide binding + β₂m

Cell surface

Peptide–MHC class I

CD8⁺ T cell

Recognition

Slide 25 · CD8 binds the class I α3 domain

CD8⁺ T lymphocyte

T-cell receptor (TCR)

Recognizes peptide + MHC

Peptide–MHC class I

CD8 coreceptor

Binds the α3 domain of class I

Schematic: TCR and coreceptor have distinct contacts

Slide 26 · The TCR and CD8 make distinct molecular contacts

The TCR recognizes the composite peptide–MHC class I complex.

CD8 binds a nonpolymorphic region of the class I heavy chain.

CD8 acts as a coreceptor during antigen recognition and T-cell activation.

The antigenic peptide determines specificity; The MHC class determines coreceptor pairing.

Slide 27 · MHC class I restriction defines CD8⁺ recognition

Compatible recognition

Incompatible context

Antigen peptide is displayed by class I

Peptide by itself is not the normal target

TCR engages peptide–class I

Class II does not substitute for class I

CD8 associates with class I α3

The class I restriction requirement is not met

Slide 28 · Recognition by CD8⁺ cells supports cytotoxic defense

Peptide–class I

On infected or tumor cell

CD8⁺ recognition

Cytotoxic T lymphocyte

Target-cell killing

Removal of abnormal host cell

Class I connects intracellular antigens with CTL-mediated elimination.

Slide 29 · Why class I is expressed on virtually all nucleated cells

Viruses may infect many different nucleated cell types.

Tumors can arise from many kinds of nucleated host cells.

Broad class I display allows cytotoxic T cells to survey such cells.

Platelets also express class I MHC, as stated in the source.

Slide 30 · HLA-DP, HLA-DQ, and HLA-DR form class II loci

HLA-DP

Class II genes encoding α and β components.

HLA-DQ

Another class II gene subregion within HLA-D.

HLA-DR

A third principal class II gene subregion.

Unlike class I, the two chains of class II are both polymorphic.

Slide 31 · Class II expression is concentrated in antigen presenters

Dendritic cell

CLASS II

Macrophage

CLASS II

B lymphocyte

CLASS II

Professional antigen presentation of ingested proteins

Slide 32 · MHC class II contains an α chain and a β chain

α1

β1

Bound peptide

α2

β2

Schematic: Peptide groove formed by α1 and β1

Both α and β chains vary

α1 / β1 create groove

α2 / β2 form lower domains

β2 contacts CD4

Slide 33 · Class II forms its peptide groove from α1 and β1

α1

β1

Bound peptide

α2

β2

Schematic: Peptide groove formed by α1 and β1

Both α and β chains vary

α1 / β1 create groove

α2 / β2 form lower domains

β2 contacts CD4

Slide 34 · Both class II chains contribute to polymorphism

The noncovalently associated class II α and β chains are both polymorphic.

The antigen-binding cleft depends on the α1 and β1 domains.

Most allelic differences described in the text occur in this peptide-binding region.

Variation therefore changes which extracellular-derived peptides can be presented.

Slide 35 · Class II antigens originate from internalized proteins

Extracellular protein

Microbe or soluble protein

Cellular uptake

Antigen internalization

Endosomal compartment

Antigen proteolysis

Class II complex

Peptide presentation

The uptake route distinguishes class II presentation from class I processing.

Slide 36 · Endosomes and lysosomes digest internalized antigens

After uptake, proteins enter intracellular vesicular compartments.

Proteolysis in endosomes or lysosomes generates peptide fragments.

These peptides become available for loading onto class II molecules.

Slide 37 · Class II loading occurs in intracellular vesicles

Internalized antigen

Protein in vesicle

Proteolytic digestion

Peptides generated

Class II binding

Peptides associate with heterodimer

Peptide–class II complexes are assembled within vesicular compartments.

Slide 38 · Class II complexes travel to the cell surface

Peptide + MHC II

Stable vesicular complex

Vesicle transport

Movement to plasma membrane

Surface display

Recognition by helper T cells

The same physical logic applies: Peptide becomes visible only when displayed by MHC.

Slide 39 · Class II processing: Integrated pathway

External source

Microbial or other protein

Uptake

Endosome or lysosome

Proteolysis

Peptide generated

Class II binding

Stable heterodimer complex

CD4⁺ T cell

Recognition

Slide 40 · CD4 binds the class II β2 domain

CD4⁺ helper T lymphocyte

T-cell receptor (TCR)

Recognizes peptide + MHC

Peptide–MHC class II

CD4 coreceptor

Binds the β2 domain of class II

Schematic: TCR and coreceptor have distinct contacts

Slide 41 · MHC class II restriction defines helper recognition

CD4⁺ cells recognize antigen in association with MHC class II.

The TCR engages the peptide–class II complex.

CD4 acts as a coreceptor by binding the class II β2 domain.

Helper function is therefore coupled to the class II presentation pathway.

Slide 42 · Dendritic cells link antigen capture to T-cell priming

Tissue dendritic cell

Captures microbial proteins

Migration

Carries antigens to lymph node

MHC display

Presented peptide + costimulators

Naive T cell

Recognition and activation

Antigen capture and lymphoid-organ presentation concentrate encounters with rare naive T cells.

Slide 43 · Macrophages present ingested microbial antigens

Phagocytosis

Macrophage takes up microbe

Class II display

Microbial peptides presented

CD4⁺ T helper

Recognition of displayed peptide

Macrophage activation

Improved killing of ingested microbes

Class II display enables helper cells to act on the same phagocyte containing the microbe.

Slide 44 · B lymphocytes present protein antigens to helper T cells

BCR captures protein

Antigen-specific uptake

Peptide–class II

B-cell antigen display

Helper T cell

CD40L + cytokines

B-cell response

Antibody production

B cells require linked peptide presentation to receive cognate help for many protein antigens.

Slide 45 · CD4⁺ helper cells coordinate distinct effector arms

Macrophage help

Helper T cells activate phagocytes that have ingested microbes.

B-cell help

Helper cells drive antibody responses to protein antigens.

Immune direction

Class II links internalized antigens to protective effector programs.

Slide 46 · Class I and class II differ at every functional level

Property

MHC class I

MHC class II

Principal gene region

HLA-A, -B, -C

HLA-DP, -DQ, -DR

Protein chains

α heavy chain + β₂m

Polymorphic α + β chains

Main peptide origin

Cytosolic proteins

Internalized proteins

Coreceptor

CD8

CD4

T-cell program

Cytotoxic killing

Helper responses

Slide 47 · Different intracellular compartments determine peptide origin

Cytosolic proteins

Internalized proteins

MHC class I

MHC class II

CD8⁺ CTL: Kills affected host cell

CD4⁺ T helper: Activates effector responses

Slide 48 · T-cell identity predicts the presenting MHC class

T cell

Coreceptor target

MHC-restricted recognition

Typical function

CD8⁺

Class I α3

Peptide–MHC I

CTL killing

CD4⁺

Class II β2

Peptide–MHC II

Macrophage and B-cell help

Slide 49 · Peptide display alone does not complete naive T-cell activation

Signal 1

Signal 2

TCR recognizes peptide displayed by MHC

APC provides costimulatory molecules

Specifies the antigen recognized by the T cell

Supports naive T-cell activation in response to danger

Slide 50 · CD80/CD86–CD28 is a principal costimulatory interaction

Innate detection

Microbe or adjuvant activates APC

APC costimulator

CD80 / CD86 (B7)

T-cell receptor

CD28

T-cell activation

Together with antigen recognition

Costimulation is mechanistically separate from the peptide–MHC–TCR interaction.

Slide 51 · HLA haplotypes are inherited gene combinations

An HLA haplotype is the set of HLA alleles on one chromosome.

Each individual inherits one HLA haplotype from each parent.

The inherited set is usually transmitted as a block.

Together the two haplotypes determine an individual’s HLA profile.

Slide 52 · HLA haplotypes pass from each parent to offspring

Parent 1

Parent 2

H1

H2

H3

H4

Possible offspring combinations (one haplotype from each parent)

H1 + H3

H1 + H4

H2 + H3

H2 + H4

If two siblings inherit the same pair: 1 of 4 possible pairings under standard assumptions

Slide 53 · Both parental HLA sets are generally expressed

Maternal chromosome

Paternal chromosome

Contains one inherited HLA haplotype

Contains the second inherited HLA haplotype

Contributes HLA molecules to cell surface

Also contributes HLA molecules to surface

Slide 54 · HLA-identical siblings: The one-in-four principle

Each sibling inherits one of two parental haplotypes from each parent.

With usual inheritance assumptions, four parental combinations are equally likely.

The probability that two siblings share both inherited haplotypes is 1 in 4.

This probability is for a specified sibling pair, not a guarantee in a family.

Slide 55 · Extreme HLA diversity complicates organ matching

Polymorphic loci

Many population alleles

Distinct haplotypes

Most people differ

Foreign HLA on graft

Immune recognition

Potential rejection

Transplant barrier

The original discovery of MHC molecules came from transplant compatibility.

Slide 56 · Sibling HLA matching has practical transplant importance

Close relatives may share complete HLA haplotypes.

Siblings are often evaluated as potential donors when clinically appropriate.

The text specifically cites kidney and hematopoietic stem cell transplantation.

The HLA profile is one part of donor–recipient compatibility assessment.

Slide 57 · Polymorphism broadens species-level immune recognition

An HLA molecule binds only a subset of possible antigenic peptides.

Different alleles broaden the peptide repertoire across a population.

The text proposes that this diversity offers protection against diverse infections.

The advantage occurs at population level even when individuals differ in responsiveness.

Slide 58 · Peptide binding constrains each individual’s T-cell response

Same antigen protein

Derived peptide

HLA variant A

HLA variant B

Peptide can bind

Peptide binding differs

Illustrates allele-dependent peptide presentation, not an absolute binding prediction

Slide 59 · HLA variation may determine protection from a microbe

Inherited HLA variant

Peptide-binding capacity

Microbial peptide

Can be displayed

Helper-cell recognition

Immune response triggered

Protective response

May enhance resistance

The text presents this as a plausible consequence of antigen binding, not a universal guarantee.

Slide 60 · HLA variation can also predispose to allergic responses

Inherited class II

Binds environmental peptide

Peptide display

For example, ragweed pollen

CD4⁺ recognition

Allergen-reactive response possible

Susceptibility

Allergic response may result

Antigen presentation is a susceptibility factor, not sufficient proof of clinical allergy.

Slide 61 · HLA–autoimmunity associations require causal caution

Several autoimmune and other diseases associate with particular HLA alleles.

Peptide-binding differences provide a biologically plausible connection.

An association does not imply that an allele alone produces disease.

Additional mechanisms under autoimmunity later in the chapter.

Slide 62 · Case: A cell containing replicating virus

A nucleated epithelial cell contains viral proteins in its cytosol. The immune system must identify this infected cell.

Which MHC class is expected to display viral peptides, and which T-cell subset recognizes them?

Predict the pathway and the responding T-cell subset

Slide 63 · Case interpretation: Cytosolic viral peptides

MHC class I → CD8⁺ cytotoxic T lymphocyte

Viral proteins enter the cytosolic processing pathway.

Peptide display on class I permits TCR recognition with CD8 coreceptor binding.

A CTL response can eliminate the infected host cell.

Slide 64 · Case: A macrophage has ingested bacteria

A tissue macrophage has engulfed microbes and is displaying peptides derived from the ingested organisms.

Which MHC class presents these peptides, and what type of T-cell assistance follows?

Predict the pathway and the responding T-cell subset

Slide 65 · Case interpretation: Internalized microbial proteins

MHC class II → CD4⁺ helper T cell

Internalized proteins are processed in endosomal or lysosomal vesicles.

The class II β2 domain engages the CD4 coreceptor.

Helper T-cell responses can activate the macrophage to destroy ingested microbes.

Slide 66 · Follow antigen location to the appropriate immune response

Cytosolic proteins

Internalized proteins

MHC class I

MHC class II

CD8⁺ CTL: Kills affected host cell

CD4⁺ T helper: Activates effector responses

Slide 67 · Core principles of HLA-mediated antigen display

MHC molecules display antigen-derived peptides rather than intact protein.

Class I: Cytosolic peptides → CD8⁺ cytotoxic T-cell recognition.

Class II: Internalized proteins → CD4⁺ helper T-cell recognition.

HLA polymorphism changes peptide repertoire and transplant compatibility.

HLA haplotypes are inherited from both parents and shape immune variation.

Slide 68 · Primary reference and source boundaries

Robbins, Cotran & Kumar

Pathologic Basis of Disease · 11th edition (2026)

Chapter 6 · Diseases of the Immune System

MHC antigen-presentation section, pp. 174–176

Supporting context: lymphocyte receptors and activation, pp. 171–178