Human Leukocyte Antigen (HLA) and MHC Explained

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-09-20

The major histocompatibility complex (MHC) is a dense cluster of genes whose protein products bind short peptide fragments and display them on the cell surface for inspection by T cells. In humans, those genes and their proteins are called the human leukocyte antigen (HLA) system, while the general term MHC applies across all jawed vertebrates, including dogs, cattle, horses and fish.

This system matters because it sits at the junction of nearly every adaptive immune decision. It determines which cells can be killed, which antibodies get help, why an organ from a sibling is tolerated better than one from a stranger, and why certain HLA alleles appear again and again in autoimmune and inflammatory diseases. For veterinary students the same logic applies across species, because the dog, cow and horse carry their own MHC orthologues that behave in the same fundamental way.

The MHC Complex: Definition and Naming

The MHC complex is a genomic region, not a single gene. It contains dozens of loci packed together on one chromosome, and the proteins they encode are the major histocompatibility proteins that define tissue identity. The name comes from the original observation that tissue grafts between genetically different animals were rejected, and that this rejection was governed by a set of "histocompatibility" genes. The histocompatibility complex MHC is therefore the genetic basis of graft rejection and, more broadly, of antigen presentation.

Three naming layers are worth separating clearly.

• MHC is the general, cross-species term for the gene region and its proteins.
• HLA is the human MHC. The name reflects the fact that these antigens were first detected on human leukocytes.
• Species orthologues carry their own acronyms. Dogs have DLA (dog leukocyte antigen), cattle have BoLA (bovine leukocyte antigen), and horses have ELA (equine leukocyte antigen). Pigs have SLA, cats have FLA, and even fish have MHC genes, as shown by work on the grouper immunoproteasome subunit PSMB9, which participates in MHC class I-restricted antiviral immunity [1].

The MHC region shows conserved features and lineage-specific rearrangements across jawed vertebrates. A re-annotation of the axolotl MHC found a typical tetrapod organization: a core MHC region with several expressed MHC class I genes tightly linked to their antigen processing genes, and single loci of MHC class II genes [2]. That architecture, class I genes sitting next to the machinery that feeds them peptides, is a recurring theme.

Why Antigen Presentation Matters

The immune system must distinguish a vast diversity of pathogens while avoiding harmful responses to self. MHC proteins provide the structural platform for displaying short peptide fragments derived from intracellular or extracellular proteins, and T-cell receptors (TCRs) on T lymphocytes read those displayed peptides [3]. Without MHC, T cells would be blind. The MHC molecule is the display stand, the peptide is the merchandise, and the TCR is the customer that decides whether to respond.

The diversity of MHC genes, generated through polymorphism and codominant expression, lets a single individual present an enormous range of peptides, which strengthens immune surveillance. The same diversity creates barriers to organ transplantation [3]. Those two consequences, protection and rejection, come from the same biology.

MHC Class I and MHC Class II: Structure and Function

MHC class I and class II molecules are specialized for antigen presentation. Unlike TCRs, which have great variability, the MHC-I and MHC-II molecules themselves have essentially no variability within an individual [4]. Their job is to bind and display, not to recognize. The peptide-binding groove is the business end, and its shape determines which peptides fit.

MHC Class I

The MHC I complex is expressed on nearly all nucleated cells. It presents endogenous peptides, meaning fragments derived from proteins made inside the cell, including viral proteins and abnormal self-proteins. MHC class I molecules present endogenous peptides to CD8+ cytotoxic T cells [3]. When a CD8+ T cell recognizes its peptide on MHC I, it can kill the target cell.

Peptide loading onto MHC I depends on the proteasome and the transporter associated with antigen processing (TAP). The immunoproteasome subunit PSMB9 is a catalytic component that supports antigen processing and MHC class I-restricted cellular immunity, and its overexpression in grouper was associated with reduced viral burden during two different virus infections, alongside enhanced MHC I-associated transcriptional activity [1]. This conservation across fish and mammals shows how old the class I pathway is.

Cross-presentation is a special case in which exogenous antigens, taken up from outside the cell, are diverted into the MHC I pathway. This happens in dendritic cells and is important for immunity to tumors and to viruses that do not infect antigen-presenting cells. In dendritic cells, MHC class I cross-presentation involves final proteolytic peptide processing by the endosomal insulin-regulated aminopeptidase (IRAP), and the IRAP-proximal proteome remodels dramatically during phagocytosis [5]. The protein Sec22b modulates this landscape, promoting localization of MHC-I cross-presentation proteins while its absence favors MHC-II and ER-related proteins, suggesting a Sec22b-dependent dichotomy between cross-presentation and antigen degradation [5].

MHC Class II

MHC class II is expressed mainly on professional antigen-presenting cells: dendritic cells, macrophages and B cells. It presents exogenous peptides, fragments derived from material the cell has taken up and processed in endosomes. MHC class II molecules present exogenous peptides to CD4+ helper T cells [3]. When a CD4+ T cell recognizes its peptide on MHC II, it orchestrates help for B cells and CD8+ T cells rather than killing directly.

Recombinant MHC II proteins are used to analyze peptide-binding interactions, detect antigen-specific T cells, and test for donor-specific anti-HLA antibodies in organ transplantation. Production of soluble extracellular domains of thirteen different MHC II proteins across the three isotypes HLA-DR, DQ and DP has been achieved in plants, with the HLA-DRA*01:01/DRB1*01:01 heterodimer linked to either a class II-associated invariant chain peptide (CLIP) or an influenza hemagglutinin peptide as a model [6]. That kind of reagent work underpins both diagnostics and transplant monitoring.

The Comparison Table

MHC Class III and the Wider Gene Region

The MHC region is not limited to class I and class II. The class III region sits between them and contains genes that do not present antigen at all. These include complement components such as C2, C4 and factor B, plus tumor necrosis factor and heat shock proteins. Class III genes are still part of the histocompatibility complex MHC because they are physically linked within the same region and are inherited together, but their products do different jobs.

The practical consequence is linkage. Because class I, class II and class III genes sit close together, they tend to be inherited as blocks called haplotypes. A person inherits one haplotype from each parent, so each individual expresses two sets of MHC alleles, one maternal and one paternal. This codominant expression is why MHC typing produces two alleles at each locus and why siblings have a one-in-four chance of matching haplotypes.

HLA Gene Regions and Allele Nomenclature

The HLA region sits on the short arm of human chromosome 6. Classical class I genes are HLA-A, HLA-B and HLA-C. Classical class II genes are HLA-DP, HLA-DQ and HLA-DR. Nonclassical class I molecules include HLA-E, HLA-F, HLA-G, MHC-I-related protein 1 (MR1) and the CD1 family, which regulate immune surveillance, tissue homeostasis and tolerance through specialized interactions with innate and unconventional T cells [7].

Reading HLA Allele Names

HLA nomenclature uses a colon-separated string that encodes the locus, the allele group and the specific allele. Take HLA-DRA*01:01/DRB1*01:01 as an example [6].

1. HLA-DRA and HLA-DRB1 name the loci. DRA encodes the alpha chain and DRB1 the beta chain of the DR heterodimer.
2. The asterisk separates the gene name from the allele designation.
3. The first field (01) is the allele group, historically defined by serology.
4. The second field (01) distinguishes alleles within that group, defined by nucleotide sequence.
5. Additional fields can be added for synonymous substitutions and noncoding variation, but the first two fields are what most clinical reporting uses.

Because HLA-DR is a heterodimer, a full description names both chains. HLA-DQ and HLA-DP follow the same logic, with an A chain and a B chain gene.

MHC Class I vs MHC Class II: Which Cells Express Them

The expression pattern is the fastest way to keep the two classes straight.

• MHC I is on nearly all nucleated cells. Red blood cells are the classic exception because they lack a nucleus. This broad expression makes sense because any cell can become infected by a virus and needs to report it.
• MHC II is restricted to professional antigen-presenting cells. Dendritic cells are the most potent, followed by macrophages and B cells.

Expression is not fixed. In healthy mouse and human central nervous system endothelium, MHC class I expression is low and MHC class II is minimal to absent. During neuroinflammation, brain microvascular endothelial cells can acquire antigen-presenting features, predominantly in the context of strong or prolonged inflammation [8]. That shift from low to inducible expression is a general principle: MHC levels respond to the immune environment.

The epithelium is another example. In an in vitro bronchial epithelial model, MHC class II machinery was significantly suppressed, with CIITA down by a log fold change of -0.90, HLA-DMA down by -1.11 and HLA-DMB down by -1.12, while MHC class I was preserved as indicated by increased B2M [9]. CIITA is the master transcriptional regulator of class II, so its suppression explains the coordinated drop across the class II genes.

CD8 and CD4 Restriction

Restriction is the rule that a T cell only sees its peptide when it is presented by the correct MHC class. CD8 binds MHC class I. CD4 binds MHC class II. This pairing is established during T-cell development and is the reason the two subsets have different jobs.

The consequences are practical. If you want to activate cytotoxic T cells against a tumor or virus, you need MHC class I-restricted peptides. If you want helper T cells, you need MHC class II-restricted peptides. In melanoma and colon carcinoma mouse models, co-delivering MHC class I and class II peptides on dual-antigen nanoparticles increased proliferation of both cytotoxic and helper T cells relative to single-antigen nanoparticles, and produced up to 8-fold higher interferon-gamma secretion [10]. Immunization with the dual-antigen nanoparticles prolonged survival, with 40% of melanoma-bearing and 71% of colon carcinoma-bearing mice surviving, compared with 0% and 13% in the comparison groups [10]. Delivering both classes together outperformed delivering either alone.

The relationship is not strictly one-way. MHC class I on target cells also regulates CD4+ T cell-mediated immunity. In graft-versus-host disease and tumor models, the absence of MHC class I on target cells significantly increased their susceptibility to CD4+ T cell cytotoxicity, apparently through heightened sensitivity to ferroptosis [11]. This revises the textbook picture and shows that class I does more than serve CD8+ T cells.

How the System Is Studied and Tested

Several methods let researchers and clinicians observe MHC biology directly.

• Immunopeptidomics identifies the peptides actually bound to MHC molecules. Phosphoproteomics and immunopeptidomics show that phosphorylated peptides are naturally processed and presented by MHC class I and II molecules and can elicit robust T-cell responses [12]. These epitopes influence proteasome cleavage, TAP transport and MHC loading.
• Proximity biotinylation maps the protein neighborhood of a compartment. Expressing an IRAP-TurboID fusion in a dendritic cell line allowed analysis of luminal proteins associated with IRAP at steady state and during phagocytosis [5].
• Phagosome purification protocols recover phagosomes from dendritic cells, fix them, rupture the membrane and expose ovalbumin-loaded MHC molecules to antigen-specific T cells, allowing colorimetric evaluation of CD8+ and CD4+ T cell activation [13].
• Recombinant MHC reagents provide defined peptide-MHC complexes for binding studies and antibody detection [6].
• Transcriptomic profiling quantifies MHC gene expression. The bronchiectasis analysis combined bulk lung RNA-sequencing with an epithelial microarray dataset and found coordinated suppression of class II machinery alongside preserved class I [9].

Clinical Relevance, Limitations and Common Mistakes

Transplantation Matching

The extraordinary polymorphism of MHC genes creates barriers to organ transplantation [3]. Matching donor and recipient at HLA loci reduces the chance that the recipient's immune system will recognize the graft as foreign. Because class I and class II genes are inherited as haplotypes, a sibling who shares both haplotypes is a much better match than an unrelated donor. Donor-specific anti-HLA antibodies are a major concern, and recombinant MHC II proteins are used in clinical testing for exactly these antibodies [6].

Disease Associations

Certain HLA alleles appear repeatedly in specific diseases. The MHC-I-opathy concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC class I antigen presentation pathway. Classical examples include spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis, which are associated with certain MHC-I alleles and with variants in the antigen-processing aminopeptidases ERAP1 and ERAP2, implicating altered MHC-I peptide presentation to CD8+ T cells in pathogenesis [14]. Discrete HLA genes also associate with neurological diseases characterized by neuroinflammation and blood-brain barrier disruption [15].

In rheumatoid arthritis, single-cell transcriptomic and TCR repertoire analysis revealed shared clonally expanded cytotoxic CD8+ T cell programs, with synovial enrichment of activated effector and proliferating populations. RA-associated oral bacteria stimulate neutrophil extracellular trap formation, generating citrullinated bacterial and host proteins that can be cross-presented to CD8+ T cells via HLA class I molecules expressed by monocyte-derived dendritic cells and autoreactive B cells [16].

Cancer and Immunotherapy

MHC expression shapes cancer outcomes. Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity, and both MHC-I and MHC-II contribute to tumor control after cDC1 vaccination. Coexpression of MHC-I and MHC-II on the same cDC1 is necessary for a robust vaccine response [17]. Histone deacetylase inhibitors can also modulate the pathway. Entinostat, a class I HDAC inhibitor, induced upregulation of MHC-I and PD-L1 expression in human and murine non-small-cell lung cancer cell lines and enhanced antigen-specific CD8 T-cell responses [18].

Nonclassical MHC-I molecules are emerging therapeutic targets. HLA-E, HLA-F, HLA-G, MR1 and the CD1 family regulate immune surveillance, tissue homeostasis and tolerance, and recent advances have established these pathways as tractable targets for immunotherapy [7].

Common Mistakes

• Treating MHC and HLA as synonyms. HLA is the human MHC. The general term is MHC.
• Assuming MHC II is on all cells. It is restricted to professional antigen-presenting cells and can be induced elsewhere during inflammation.
• Mixing up the restriction rule. CD8 pairs with MHC I. CD4 pairs with MHC II.
• Forgetting class III. The class III region contains complement and cytokine genes, not antigen-presenting molecules.
• Assuming MHC molecules recognize antigen. They bind and display peptides. TCRs do the recognizing [4].
• Ignoring species differences. Dogs, cattle and horses have their own MHC systems with their own nomenclature.

Individual cases require veterinary or medical judgment, and this article is educational and is not a substitute for veterinary diagnosis or treatment.

Quick Review

1. MHC is the general term. HLA is the human version. DLA, BoLA and ELA are the dog, cattle and horse orthologues.
2. MHC class I presents endogenous peptides to CD8+ T cells and is expressed on nearly all nucleated cells.
3. MHC class II presents exogenous peptides to CD4+ T cells and is expressed mainly on dendritic cells, macrophages and B cells.
4. The class III region holds complement and cytokine genes, not antigen-presenting molecules.
5. HLA allele names use colon-separated fields, with the first two fields carrying most clinical meaning.
6. MHC polymorphism enables broad peptide presentation and creates transplantation barriers.
7. Specific HLA alleles associate with inflammatory, autoimmune and neurological diseases.

Frequently Asked Questions

What is the difference between MHC and HLA?

MHC is the general term for the gene region and its proteins across species. HLA is the specific name for the human MHC system, so every HLA gene is an MHC gene, but not every MHC gene is an HLA gene.

Which cells express MHC class I versus MHC class II?

MHC class I is expressed on nearly all nucleated cells. MHC class II is expressed mainly on professional antigen-presenting cells such as dendritic cells, macrophages and B cells, and can be induced on other cell types during inflammation.

What does CD8 versus CD4 restriction mean?

CD8 restriction means a CD8+ T cell only recognizes its peptide when presented by MHC class I. CD4 restriction means a CD4+ T cell only recognizes its peptide when presented by MHC class II.

Why does HLA matching matter for transplantation?

HLA genes are highly polymorphic, so a mismatched graft displays foreign MHC proteins that the recipient's immune system attacks. Matching at HLA loci reduces rejection risk, and siblings who share haplotypes are often the best matches.

What are MHC class III genes?

Class III genes sit between the class I and class II regions and encode complement components, tumor necrosis factor and heat shock proteins. They are part of the MHC region but do not present antigen.

Do animals have HLA?

No. Animals have their own MHC systems with different names, including DLA in dogs, BoLA in cattle and ELA in horses. The underlying biology of antigen presentation is conserved across these species.

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