18.2 Major Histocompatibility Complexes and Antigen-Presenting Cells

Major Histocompatibility Complexes (MHC)

MHC molecules are cell-surface proteins that display fragments of antigens to T cells, connecting what's happening inside a cell to the adaptive immune response outside it. Without MHC, T cells would have no way to "see" intracellular infections or foreign proteins, making this system central to how adaptive immunity works.

Structure and Expression of MHC Molecules

MHC molecules come in two classes, and the differences between them determine which T cells respond and what kind of threat gets addressed.

MHC I molecules:

• Heterodimers made of a polymorphic α chain and a non-polymorphic β2-microglobulin (light chain)
• Expressed on the surface of all nucleated cells (this means red blood cells, which lack a nucleus, don't express MHC I)
• Present intracellular antigens to CD8+ T cells. These include viral proteins (e.g., influenza nucleoprotein) and tumor antigens (e.g., melanoma-associated antigens). The α chain contains a peptide-binding groove that holds the antigenic peptide for display.
• The function here is surveillance: MHC I lets the immune system check whether a cell has been infected or has become cancerous.

MHC II molecules:

• Heterodimers of polymorphic α and β chains that together form a peptide-binding cleft
• Expression is restricted to professional antigen-presenting cells (APCs): dendritic cells, macrophages, and B cells
• Present extracellular antigens to CD4+ T cells. Examples include bacterial proteins like tetanus toxoid and other exogenous material the APC has engulfed. This stimulates helper T cell responses and downstream antibody production.

Key Antigen-Presenting Cells

Three cell types serve as professional APCs, each with a distinct role.

Dendritic cells (DCs) are the most potent APCs and the only ones that can activate naive T cells to initiate a primary immune response.

• Myeloid DCs specialize in antigen uptake, processing, and presentation to T cells in lymph nodes
• Plasmacytoid DCs produce large amounts of type I interferons (IFN-α, IFN-β) during viral infections like influenza and HIV
• DCs are also capable of cross-presentation, a process where exogenous antigens are loaded onto MHC I molecules instead of MHC II. This allows CD8+ T cells to respond to threats the DC didn't produce internally, which is critical for antiviral and antitumor immunity.

Macrophages bridge innate and adaptive immunity.

• They phagocytose and degrade pathogens (bacteria, fungi), then present processed antigens to T cells via MHC II
• They secrete pro-inflammatory cytokines (IL-1, TNF-α) and chemokines that recruit other immune cells to the site of infection
• Beyond immune defense, macrophages contribute to tissue repair and homeostasis by clearing apoptotic cells

B cells are best known for producing antibodies, but they also function as APCs.

• After binding antigen through their B cell receptor, they internalize it, process it, and present peptide fragments on MHC II to CD4+ T helper cells
• This interaction, along with co-stimulatory signals like the CD40-CD40L interaction, drives B cell activation and differentiation into antibody-secreting plasma cells

Antigen Processing and Presentation

The two MHC classes use fundamentally different pathways to load peptides. Understanding these pathways step by step is one of the most testable parts of this topic.

MHC I Pathway (Intracellular Antigens)

1. Intracellular proteins (e.g., viral proteins made by an infected cell, or mutated tumor proteins like p53) are tagged with ubiquitin and degraded by the proteasome in the cytosol.
2. The resulting peptide fragments are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP).
3. Inside the ER, peptides bind to newly assembled MHC I molecules in the peptide-binding groove.
4. The stable MHC I-peptide complex travels through the Golgi to the cell surface.
5. CD8+ cytotoxic T lymphocytes (CTLs) recognize the MHC I-peptide complex via their TCR and kill the presenting cell.

MHC II Pathway (Extracellular Antigens)

1. Extracellular antigens (e.g., bacterial proteins, allergens like pollen) are taken up by APCs through endocytosis or phagocytosis.
2. Inside the cell, antigens are degraded into peptide fragments by proteases (cathepsins) within endosomes and lysosomes.
3. Meanwhile, MHC II molecules are synthesized in the ER. During transport, an invariant chain (Ii) blocks the peptide-binding cleft to prevent premature binding of endogenous peptides.
4. MHC II molecules travel to the endosomal compartment, where the invariant chain is degraded. A small fragment called CLIP remains in the groove until it's exchanged for an antigenic peptide (facilitated by the molecule HLA-DM).
5. The stable MHC II-peptide complex moves to the cell surface, where it's recognized by CD4+ T helper cells via their TCR. This triggers helper T cell responses (Th1, Th2 differentiation) and promotes antibody production by B cells.

Genetic Basis and Diversity

MHC molecules are encoded by the HLA (Human Leukocyte Antigen) genes located on chromosome 6. These genes are among the most polymorphic in the human genome, meaning there are many different alleles in the population.

This diversity matters because each MHC variant binds a slightly different set of peptides. A population with diverse HLA types is better equipped to collectively recognize a wide range of pathogens. It also explains why individuals vary in their susceptibility to specific infections and why HLA matching is critical for organ transplantation (mismatched HLA molecules trigger graft rejection).

T Cell Recognition

T cell receptors (TCRs) don't recognize free-floating antigens. They only recognize antigenic peptides when presented in the context of an MHC molecule on an APC's surface. This principle is called MHC restriction.

• CD8+ T cells are restricted to MHC I-peptide complexes
• CD4+ T cells are restricted to MHC II-peptide complexes

Co-receptors on the T cell (CD8 or CD4) bind to conserved regions of the MHC molecule, stabilizing the interaction and ensuring the right T cell type responds to the right class of antigen. Without this TCR-MHC-peptide interaction, the adaptive immune response cannot be initiated.