What is an antigen?

What is an Antigen?

An antigen is a molecule—typically a protein, carbohydrate, or lipid—that can be recognized and bound by components of the immune system, specifically by antibodies or T cell receptors, thereby exhibiting antigenicity. 1

Core Definition and Molecular Characteristics

Antigenicity refers to the fundamental property of a substance to bind to immune system components, while immunogenicity represents the more specific ability to induce an actual immune response. 1 Not all antigens are immunogenic—some may bind immune receptors without triggering a response. 2

Physical and Chemical Properties

• Antigens vary greatly in their physicochemical features including biochemical nature, structural complexity, molecular size, foreignness, and solubility. 2
• The epitopes (the specific regions recognized by the immune system) of an antigen are located in surface areas and are approximately 880-3,300 Da in size. 2
• Antigens can be protein, carbohydrate, or lipid in nature. 2
• Soluble antigens are typically smaller than 1 nm, while particulate antigens are larger and endocytosed more efficiently. 2
• The smallest molecules capable of inducing immune responses (immunogens) are approximately 4,000-10,000 Da in size. 2

Recognition and Presentation Mechanisms

Antigens must be processed and presented by antigen-presenting cells (APCs) before T lymphocytes can recognize them. 3 This critical distinction separates antigens from simple foreign molecules:

• For CD8+ T cells: Antigens are presented on MHC class I molecules on the tumor or infected cell surface. 1
• For CD4+ T cells: Professional APCs present antigens on MHC class II molecules after processing extracellular proteins. 1
• The T cell receptor recognizes a bimolecular complex consisting of the antigenic peptide bound to the MHC molecule, not the antigen alone. 3

Processing Requirements

Antigen molecules undergo internal processing by APCs that generates immunogenic peptides. 3 These peptides then associate with histocompatibility molecules to form the surface complexes that T cells recognize. 3

Types of Antigens Based on Origin

Exogenous vs. Endogenous Antigens

• Exogenous antigens originate outside the body (pathogens, foreign proteins) and typically induce humoral immunity through antibody production. 2
• Endogenous antigens are produced within cells (viral proteins, tumor neoantigens) and typically induce cell-mediated immunity. 2

Neoantigens: A Special Category

Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. 1 These represent a particularly important class of antigens in cancer immunotherapy:

• Neoantigens arise from somatic mutations resulting in novel peptides presented on tumor cell surfaces by MHC-I molecules. 1
• They are not subject to central tolerance (thymic selection), making them ideal targets for immune recognition. 1, 4
• Only 1-2% of all somatic non-synonymous mutations are actually processed, presented, and recognized by T cells. 4
• Neoantigens can be derived from single nucleotide variants, mutational frameshifts, splice variants, gene fusions, or endogenous retroelements. 1

Antigenicity vs. Immunogenicity: Critical Distinction

Antigenicity is conferred by the expression and presentation of molecules that can be recognized by the immune system, while immunogenicity requires both antigenicity AND adjuvanticity to drive an actual adaptive immune response. 1

Factors Determining Immunogenicity

• Foreignness: The more phylogenetically distant an antigen is from the recipient, the more immunogenic it becomes. 2
• Structural complexity: Greater complexity increases antigenicity due to more numerous and varied epitopes. 2
• Peptide-MHC binding: Stability and binding affinity of the peptide-MHC complex are crucial. 1
• T cell receptor repertoire: Availability of naïve T cell clones that can recognize the antigen without having undergone clonal deletion during thymic selection. 1
• Adjuvanticity: Spatiotemporally coordinated release of danger signals (damage-associated molecular patterns or DAMPs) necessary for APC recruitment and maturation. 1

Clinical Relevance

In Infectious Disease

Bacterial and viral antigens elicit T cell responses through both adaptive and innate recognition pathways. 5 The adaptive immune response detects variable or unique single-gene products, while the innate system recognizes more conserved structures. 5

In Cancer Immunotherapy

• High neoantigen burden correlates with response to immune checkpoint blockade therapy. 1
• Protective antigens can invoke specific and enhanced adaptive immune responses, making them critical for vaccine preparation. 6
• Computational prediction of neoantigens from tumor sequencing data involves somatic mutation identification, HLA typing, peptide processing prediction, and peptide-MHC binding prediction. 1, 4

Common Pitfalls in Understanding Antigens

• Not all antigens induce immunity: Some may bind receptors but fail to trigger responses (exhibiting anergy). 2
• Context matters: Healthy cells have limited ability to drive immunogenic cell death because their antigens are typically expressed during thymic T cell development, leading to tolerance. 1
• Presentation is essential: An antigen cannot be recognized by T cells without proper processing and MHC presentation. 3
• Immunodominance limits responses: T cell reactivity may be dominated by responses to only a small subset of potential epitopes, even when many antigens are present. 1