What Is the Endogenous Antigen Presentation Pathway?

The body’s immune system requires a method to detect cells compromised by internal threats like viruses or cancer. This is accomplished through the endogenous antigen presentation pathway, a process that functions as a continuous internal surveillance system. This pathway allows the immune system to check the health of nearly every cell by examining a sample of the proteins being made inside them. It identifies and flags any cell with internal threats, marking it for elimination.

Processing Antigens Within the Cell

All nucleated cells continuously break down a portion of the proteins they produce, whether normal self-proteins or foreign ones from an invading virus. This process begins when proteins are marked for disposal with a small tag called ubiquitin. This tagging directs the protein to a cellular machine known as the proteasome, which functions like a molecular shredder, chopping the protein into small fragments called peptides. These peptides range from eight to sixteen amino acids in length.

Once generated in the cytoplasm, these peptides are moved to another location for display. They are transported into a specialized compartment called the endoplasmic reticulum. This transport is handled by a protein complex embedded in the endoplasmic reticulum’s membrane called the Transporter associated with Antigen Processing, or TAP. The TAP transporter selectively moves the peptide fragments into the endoplasmic reticulum in an energy-dependent process.

Presenting Antigens to the Immune System

Inside the endoplasmic reticulum, peptide fragments are met by display molecules called Major Histocompatibility Complex (MHC) Class I molecules. These molecules act as molecular billboards, waiting to be loaded with a peptide. Helper proteins, known as chaperones, assist in the stable folding of the MHC Class I molecule and its loading. One such chaperone, tapasin, physically links the MHC molecule to the TAP transporter, facilitating the efficient capture of a peptide.

After a peptide is successfully loaded onto the MHC Class I molecule, the stable complex is ready for its journey. It travels from the endoplasmic reticulum through the Golgi apparatus and is then shuttled to the cell’s outer surface. Once at the surface, the MHC Class I molecule embeds in the cell membrane, displaying the peptide it carries. This presentation serves as a signal to patrolling immune cells, specifically Cytotoxic T Lymphocytes (CD8+ T-cells).

Triggering Cell Elimination

The continuous display of peptides on the cell surface allows the immune system to monitor cellular health. When a Cytotoxic T-cell encounters a cell, it uses its T-cell receptor to inspect the presented peptide. If the T-cell recognizes the peptide as a normal “self” peptide, it disengages and leaves the healthy cell unharmed. This prevents the immune system from attacking its own tissues.

If the Cytotoxic T-cell detects a foreign or abnormal peptide, such as one from a viral protein or a cancerous mutation, it becomes activated. This recognition signals that the cell is compromised. The activated T-cell then eliminates the target cell by inducing apoptosis, or programmed cell death. It releases molecules like perforin, which creates pores in the target cell’s membrane, and granzymes, which enter to instruct the cell to self-destruct.

The Exogenous Pathway Distinction

The endogenous pathway can be contrasted with its counterpart, the exogenous pathway. While the endogenous system deals with internal threats, the exogenous pathway handles external threats like bacteria that are engulfed by specialized immune cells. These external invaders are broken down inside vesicular compartments, not in the cytoplasm by the proteasome.

The resulting peptides are loaded onto a different display molecule, MHC Class II. These are presented on the surface of professional antigen-presenting cells, like dendritic cells. Their purpose is to activate Helper T-cells (CD4+ T-cells), not to trigger immediate cell killing. These helper cells coordinate the broader immune response rather than destroying target cells themselves.

Clinical Significance of the Pathway

The endogenous antigen presentation pathway is significant for human health and disease. Many viruses have evolved mechanisms to evade detection by this system. For instance, some viruses produce proteins that block the TAP transporter, preventing viral peptides from reaching the endoplasmic reticulum. Others interfere with the surface expression of MHC Class I molecules, making the infected cell invisible to Cytotoxic T-cells.

This pathway is also important in modern cancer treatments. Cancer cells often produce abnormal proteins due to genetic mutations, and peptides from these proteins are displayed on MHC Class I molecules. While this should mark them for destruction, cancer cells can suppress the T-cell response. Cancer immunotherapies, such as checkpoint inhibitors, work by restoring the T-cells’ ability to attack cancer cells presenting these tumor peptides. By blocking the “off” signals cancer cells use, these therapies utilize the endogenous pathway to fight cancer.