The core of the immune system’s protective function is the antigen. An antigen is any molecule, typically a protein or fragment of one, that is recognized by the immune system and can provoke a defensive response. The primary challenge for the body is the continuous discernment between “self” molecules, which belong to the body, and “non-self” molecules, which represent foreign invaders or abnormal internal components. This distinction is managed through a complex series of production and processing steps that prepare these molecules for display to specialized immune cells.
The Two Primary Sources of Antigens
Antigens are broadly categorized based on their origin relative to the cell that processes them. One category is the exogenous antigens, which originate from outside the body’s cells. These typically include components from extracellular pathogens like most bacteria, fungi, parasites, or environmental substances such as toxins and pollen.
The second category is endogenous antigens, which are generated from within the cell’s own cytoplasm. These internal sources include proteins produced by viruses that have hijacked the cell’s machinery, proteins from intracellular bacteria, or aberrant, mutated proteins indicative of a cancerous transformation. Defining these two sources determines which specific cellular pathway will be used for processing and presentation.
Processing External Threats (MHC Class II)
Antigens derived from outside the cell are handled by the exogenous pathway, which utilizes specialized immune cells known as Antigen Presenting Cells (APCs), such as macrophages, dendritic cells, and B cells. This process is centered around the Major Histocompatibility Complex Class II (MHC II) molecule.
The process begins when the APC engulfs the external threat, like a bacterium, through phagocytosis or endocytosis, isolating it within a membrane-bound vesicle called an endosome or phagosome. The endosome then fuses with a lysosome, forming a phagolysosome, which is highly acidic and contains powerful hydrolytic enzymes. These enzymes begin the proteolytic degradation of the engulfed protein into smaller peptide fragments, typically 13 to 25 amino acids in length.
Simultaneously, the MHC II molecule is synthesized in the Endoplasmic Reticulum (ER) and transported to the endosomal compartment, initially bound to a chaperone protein called the invariant chain. A fragment of the invariant chain, known as CLIP, remains in the peptide-binding groove of the MHC II molecule, blocking it from binding to self-peptides in the ER. Within the phagolysosome, the MHC II molecule encounters a specialized protein that facilitates the removal of the CLIP fragment. Once the groove is clear, MHC II binds to one of the newly generated antigenic peptide fragments. The resulting peptide-loaded MHC II complex is then transported to the cell surface for display.
Generating Internal Threats (MHC Class I)
The processing of antigens generated inside the cell follows the endogenous pathway, a surveillance mechanism present in virtually all nucleated cells in the body. This pathway relies on the Major Histocompatibility Complex Class I (MHC I) molecule to report the cell’s internal state. Abnormal or viral proteins in the cytoplasm are first tagged for destruction by the attachment of a small protein called ubiquitin, a process known as ubiquitination.
These tagged proteins are then directed to the proteasome, a large, cylindrical protein complex. The proteasome degrades the proteins into short peptide fragments, typically 8 to 11 amino acids long, which is an ideal size for fitting into the MHC I binding groove. These peptide fragments must then be transported from the cytoplasm into the lumen of the Endoplasmic Reticulum (ER), where the MHC I molecules are located.
This translocation is achieved by the Transporter associated with Antigen Processing (TAP), an ATP-dependent heterodimer on the ER membrane. Once inside the ER, the peptide fragments are loaded onto the newly synthesized MHC I molecules. The assembly of the MHC I-peptide complex is facilitated by chaperone proteins like tapasin, which links the MHC I molecule directly to the TAP transporter. The fully assembled peptide-MHC I complex then travels through the Golgi apparatus to the cell surface for display.
The Final Display and Recognition
The distinct processing pathways, MHC I and MHC II, dictate the appropriate subsequent immune response. The purpose of this molecular display is to present the processed antigen to T lymphocytes, initiating the adaptive immune response.
The MHC I display, generated from internal threats, is recognized exclusively by cytotoxic T cells (CD8+ T cells). When a cytotoxic T cell recognizes the foreign peptide on the MHC I molecule, it signals that the cell is infected or cancerous and must be destroyed. This action prevents the intracellular pathogen, such as a virus, from replicating and spreading to neighboring cells.
Conversely, the MHC II display, generated from external threats, is recognized exclusively by helper T cells (CD4+ T cells). Recognition of the MHC II-peptide complex activates the T cell. The activated helper T cell releases signaling molecules called cytokines, which coordinate and amplify the overall immune response. This includes stimulating B cells to produce antibodies or activating macrophages to enhance their killing ability, thereby orchestrating the defense against pathogens outside of the cells.