Antigen Capture and Presentation: Foundations of Immunology

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Antigen Presenting Cells and Adaptive Immunity

Overview of Adaptive Immunity

Adaptive immunity is a specialized defense mechanism characterized by specificity and memory. It involves two main types of receptors—antibodies and T cell receptors—and is divided into humoral (B cell-mediated) and cell-mediated (T cell-mediated) responses.

Specificity: Adaptive immunity targets specific antigens using unique receptors.
Memory: The immune system "remembers" previous encounters, enabling a faster response upon re-exposure.
Receptors: Only two types—antibody (B cell receptor) and T cell receptor.
Types of Responses: Humoral (B cells) and cell-mediated (T cells).

Comparison of innate and adaptive immunity

Antigen Presenting Cells (APCs)

Antigen presenting cells are essential for initiating adaptive immune responses. They display peptide fragments of protein antigens bound to major histocompatibility complex (MHC) molecules on their surface, activating antigen-specific T cells.

Definition: Cells that present peptide-MHC complexes and express costimulatory molecules.
Main Types: Dendritic cells, macrophages, and B lymphocytes.
Function: Activate T cells by presenting antigens in the context of MHC molecules.

Table comparing dendritic cells, macrophages, and B lymphocytes as APCs

Antigen Recognition by T Lymphocytes

T lymphocytes recognize short peptide antigens presented by MHC molecules. There are two classes of MHC molecules, each interacting with different T cell subsets:

MHC Class I: Presents to CD8+ T cells (cytotoxic T cells).
MHC Class II: Presents to CD4+ T cells (helper T cells).
MHC Restriction: Each T cell recognizes a specific peptide-MHC combination.

Diagram of T cell receptor interaction with MHC and peptide

Antigen Capture and Migration by Dendritic Cells

Role of Dendritic Cells

Dendritic cells are the most efficient APCs for initiating T cell responses. They capture antigens that enter through epithelial barriers and transport them to secondary lymphoid organs, such as lymph nodes and spleen, where they present the antigens to naïve T cells.

Antigen Capture: Dendritic cells use membrane receptors to bind microbes and antigens.
Activation: Triggered by innate immune signals (e.g., TLRs), leading to cytokine production (TNF, IL-1).
Maturation and Migration: Upregulate CCR7, migrate to T cell zones in lymphoid organs, and increase MHC expression.

Diagram of antigen capture and migration to lymph node Steps of dendritic cell antigen capture, migration, and presentation

Major Histocompatibility Complex (MHC) Molecules

Genetics and Structure of MHC

The MHC is a cluster of genes encoding membrane proteins that present peptide antigens to T cells. In humans, these are called human leukocyte antigens (HLAs). MHC genes are highly polymorphic and co-dominantly expressed.

Class I Genes: HLA-A, HLA-B, HLA-C (expressed on all nucleated cells).
Class II Genes: HLA-DP, HLA-DQ, HLA-DR (expressed mainly on dendritic cells, macrophages, and B cells).
Polymorphism: High variability ensures diverse antigen presentation.
Haplotype: The set of MHC genes on each chromosome.

Diagram of human and mouse MHC loci

Structure of MHC Class I and II Molecules

MHC class I and II molecules have distinct structural features that determine their function in antigen presentation.

Class I: Composed of an α chain (with α1, α2, α3 domains) and β2-microglobulin. The peptide-binding cleft is formed by α1 and α2 domains.
Class II: Composed of α and β chains, each with two domains (α1, α2, β1, β2). The peptide-binding cleft is formed by α1 and β1 domains.

Structure of MHC class I and II molecules Structure of MHC class II molecule

Peptide Binding to MHC Molecules

Peptides bind to MHC molecules through noncovalent interactions. Specific amino acids in the peptide, called anchor residues, fit into pockets in the MHC molecule, stabilizing the complex. Other residues are recognized by T cell receptors.

Diagram of peptide binding to MHC and T cell receptor

Characteristics of Peptide-MHC Interactions

One peptide at a time: Each MHC molecule displays a single peptide.
Broad specificity: MHC molecules can bind many different peptides.
Stable expression: Requires peptide binding.
Slow off-rate: Peptide-MHC complexes are stable on the cell surface.

Table of features and significance of peptide-MHC interactions

Antigen Processing and Presentation Pathways

Overview of Antigen Processing

Antigen processing refers to the generation of peptide fragments from proteins, which are then loaded onto MHC molecules for presentation to T cells. The pathway depends on the origin of the antigen:

Cytosolic proteins: Processed by proteasomes and presented by MHC class I to CD8+ T cells.
Extracellular proteins: Internalized by APCs, processed in endosomes/lysosomes, and presented by MHC class II to CD4+ T cells.

Diagram of class I and class II MHC antigen processing pathways

Processing of Cytosolic Antigens (MHC Class I Pathway)

Source: Viruses, intracellular bacteria, misfolded proteins, and some nuclear proteins.
Proteolysis: Ubiquitin-proteasome pathway degrades proteins into peptides.
Transport: Peptides are transported into the endoplasmic reticulum (ER) by TAP.
Assembly: Peptides bind to class I MHC molecules in the ER, facilitated by tapasin.
Surface Expression: Peptide-MHC complexes are transported to the cell surface for recognition by CD8+ T cells.

Diagram of cytosolic antigen processing and presentation Diagram of proteasome-mediated protein degradation Diagram of peptide transport into ER by TAP Assembly of peptide-MHC class I complexes in ER Surface expression of peptide-MHC class I complexes

Processing of Internalized Antigens (MHC Class II Pathway)

Uptake: Extracellular proteins are internalized by endocytosis, pinocytosis, or phagocytosis.
Proteolysis: Proteins are degraded in endosomes/lysosomes by cathepsins.
Biosynthesis: Class II MHC α and β chains are synthesized in the ER, associated with invariant chain (Ii) to prevent premature peptide binding.
Association: Ii is degraded, leaving CLIP; HLA-DM facilitates peptide exchange, allowing antigenic peptides to bind MHC II.
Surface Expression: Stable peptide-MHC II complexes are transported to the cell surface for recognition by CD4+ T cells.

Uptake of extracellular proteins by APCs Proteolysis of antigens in lysosomes Biosynthesis and transport of class II MHC molecules Association of processed peptides with class II MHC molecules Expression of peptide-class II MHC complexes on cell surface

Cross-Presentation

Cross-presentation (cross-priming) is a process where dendritic cells present extracellular antigens on MHC class I molecules, enabling activation of CD8+ T cells. This is crucial for immune responses against viruses and tumors that do not infect dendritic cells directly.

Diagram of cross-presentation by dendritic cells

Physiological Significance of MHC-Associated Antigen Presentation

MHC restriction ensures that T cells respond only to cell-associated antigens, providing a specialized response to both extracellular and intracellular pathogens. The segregation of class I and class II pathways allows the immune system to tailor responses to the nature of the pathogen.

Diagram of physiological significance of MHC-associated antigen presentation