Antigen presentation
Overview
Antigen presentation is a critical immunological process that involves the display of antigens on the surface of cells, facilitating the recognition and response by the immune system. This process is essential for the activation of T cells, which are pivotal in orchestrating the adaptive immune response. Antigen presentation is primarily carried out by specialized cells known as antigen-presenting cells (APCs), which include dendritic cells, macrophages, and B cells. These cells process and present antigens via major histocompatibility complex (MHC) molecules, which are crucial for the recognition by T cell receptors (TCRs).
Mechanisms of Antigen Presentation
Antigen presentation involves several complex mechanisms that ensure the immune system can effectively identify and respond to pathogens. The process can be broadly divided into two pathways: the endogenous pathway and the exogenous pathway.
Endogenous Pathway
The endogenous pathway is responsible for presenting intracellular antigens, typically derived from proteins synthesized within the cell. This pathway is primarily associated with MHC class I molecules, which present antigens to CD8+ cytotoxic T cells. Proteins within the cell are degraded into peptides by the proteasome, a large protease complex. These peptides are then transported into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP). Within the ER, peptides are loaded onto MHC class I molecules, which are then transported to the cell surface for presentation.
Exogenous Pathway
The exogenous pathway involves the presentation of extracellular antigens that have been internalized by the cell. This pathway is associated with MHC class II molecules, which present antigens to CD4+ helper T cells. Antigens are taken up by APCs through processes such as phagocytosis or receptor-mediated endocytosis. Once internalized, antigens are degraded into peptides within endosomal compartments. MHC class II molecules, synthesized in the ER, are transported to these compartments, where they bind to the peptides. The MHC class II-peptide complexes are then transported to the cell surface for presentation.
Role of Antigen-Presenting Cells
Antigen-presenting cells play a pivotal role in the immune response by bridging the innate and adaptive immune systems. Each type of APC has unique characteristics and functions:
Dendritic Cells
Dendritic cells are considered the most potent APCs due to their ability to activate naive T cells. They are strategically located in tissues that are in contact with the external environment, such as the skin and mucosal surfaces. Upon encountering antigens, dendritic cells undergo maturation, characterized by increased expression of MHC molecules and co-stimulatory molecules. They then migrate to lymphoid tissues, where they present antigens to T cells.
Macrophages
Macrophages are versatile cells involved in both innate and adaptive immunity. They can phagocytose pathogens and present antigens to T cells. Macrophages are particularly important in presenting antigens to memory T cells, which have been previously activated and are involved in secondary immune responses.
B Cells
B cells are unique among APCs as they can present antigens specifically recognized by their B cell receptors (BCRs). This specificity allows B cells to present antigens to helper T cells, which in turn provide the necessary signals for B cell activation and differentiation into plasma cells that produce antibodies.
Major Histocompatibility Complex
The major histocompatibility complex is a set of genes that encode proteins critical for antigen presentation. MHC molecules are highly polymorphic, allowing for a diverse range of antigen presentation across individuals, which is crucial for effective immune responses.
MHC Class I
MHC class I molecules are expressed on nearly all nucleated cells and present endogenous antigens to CD8+ T cells. The structure of MHC class I molecules includes a heavy chain and a β2-microglobulin light chain. The peptide-binding groove of MHC class I accommodates peptides typically 8-10 amino acids in length.
MHC Class II
MHC class II molecules are primarily expressed on professional APCs and present exogenous antigens to CD4+ T cells. These molecules consist of two chains, α and β, both of which contribute to the peptide-binding groove. MHC class II molecules can accommodate longer peptides, typically 13-18 amino acids in length.
Cross-Presentation
Cross-presentation is a specialized process by which exogenous antigens are presented on MHC class I molecules. This mechanism is crucial for the activation of CD8+ T cells against pathogens that do not directly infect APCs. Dendritic cells are particularly adept at cross-presentation, which involves the uptake of extracellular antigens, their processing in the cytosol, and subsequent presentation on MHC class I molecules.
Immunological Synapse
The immunological synapse is the interface between an APC and a T cell, where antigen presentation occurs. This synapse is characterized by a highly organized structure that facilitates effective communication between the two cells. It involves the clustering of TCRs, MHC molecules, co-stimulatory molecules, and adhesion molecules, ensuring a stable and efficient interaction.
Co-Stimulation and T Cell Activation
For effective T cell activation, antigen presentation must be accompanied by co-stimulatory signals. APCs express co-stimulatory molecules such as CD80 and CD86, which interact with CD28 on T cells. This second signal is crucial for T cell activation, proliferation, and differentiation. In the absence of co-stimulation, T cells may become anergic, leading to immune tolerance.
Antigen Processing and Presentation in Disease
Defects in antigen processing and presentation can lead to various diseases, including autoimmune disorders, infections, and cancer. In autoimmune diseases, aberrant antigen presentation can result in the activation of self-reactive T cells, leading to tissue damage. In cancer, tumor cells may evade immune detection by downregulating MHC molecules, impairing antigen presentation.
Therapeutic Implications
Understanding antigen presentation has significant implications for the development of vaccines and immunotherapies. Vaccines aim to enhance antigen presentation to elicit robust immune responses. Immunotherapies, such as checkpoint inhibitors, can modulate antigen presentation pathways to enhance anti-tumor immunity.