Deep within almost every cell operates a molecular machine known as the Transporter associated with Antigen Processing, or TAP. This protein complex acts as a gatekeeper for the immune system, selecting and moving specific protein fragments from the cell’s interior.
The TAP transporter’s primary role is to provide molecular information from the cell’s interior to its surface. This allows the immune system to monitor the health of cells and distinguish them from those compromised by internal threats. This process ensures a representative sample of the cell’s internal state is always on display for inspection.
The Cellular Machinery of Antigen Presentation
The TAP transporter is a member of the ATP-binding cassette (ABC) family of transport proteins. It is a heterodimer, constructed from two separate protein subunits, TAP1 and TAP2, both of which are required for it to function. These subunits are located within the membrane of the endoplasmic reticulum (ER), a network involved in protein synthesis. Each TAP subunit has a region that spans the ER membrane and another that binds to and uses cellular energy.
Inside the cell’s cytosol, proteins are constantly broken down by the proteasome into small pieces called peptides. The TAP transporter’s job is to pump a select group of these peptides from the cytosol into the ER. This transport process is an active one, requiring energy supplied by the breakdown of a molecule called ATP.
TAP is selective about which peptides it transports, preferring those between 8 and 16 amino acids in length. This selection is based on the peptide’s length and the specific amino acids at its ends. Once these peptides are inside the ER, they are available to be loaded onto other molecules for the next step in the antigen presentation pathway.
Immune System Surveillance
Inside the ER, the newly arrived peptides are loaded onto molecules called Major Histocompatibility Complex (MHC) Class I. These MHC Class I molecules act as display platforms for the peptides. This assembly, known as the peptide-loading complex, involves several helper proteins that ensure only suitable peptides are securely bound.
Once a peptide is loaded, the MHC Class I-peptide complex is dispatched from the ER to the outer surface of the cell. Here, it becomes embedded in the cell membrane with the peptide portion exposed to the outside environment. This effectively presents a “status report” of the proteins being made inside that particular cell. Every nucleated cell in the body performs this function.
Patrolling the body are specialized immune cells called Cytotoxic T Lymphocytes (CTLs). These cells are trained to recognize the difference between normal “self” peptides and foreign or abnormal ones. As CTLs circulate, they constantly scan the MHC-peptide complexes on cell surfaces. If a CTL encounters a self-peptide, it moves on, leaving the healthy cell unharmed. If it recognizes a peptide derived from a virus or a mutated cancer protein, it initiates a response to eliminate the compromised cell.
When the Transporter Fails
Genetic mutations can render the TAP transporter non-functional, leading to a rare primary immunodeficiency disorder known as TAP deficiency syndrome. This condition is a form of Bare Lymphocyte Syndrome Type I, where the “bare” refers to the cell’s inability to display MHC Class I molecules on its surface. The disorder is autosomal recessive, meaning an individual must inherit a faulty gene for either TAP1 or TAP2 from both parents. A defect in either subunit is enough to disrupt the entire transport function.
The direct consequence of a non-working TAP transporter is that peptides cannot be pumped into the endoplasmic reticulum. Without a steady supply of peptides, MHC Class I molecules cannot be properly loaded and stabilized. This leads to a dramatic reduction in their presence on the cell surface, making the cells invisible to Cytotoxic T Lymphocytes and impairing the immune system’s ability to destroy infected cells.
This failure in antigen presentation leads to a distinct pattern of symptoms. Individuals with TAP deficiency suffer from recurrent and chronic bacterial infections of the respiratory tract, including sinusitis and pneumonia. These infections can lead to progressive lung damage and bronchiectasis. They may also develop necrotizing granulomatous lesions on their skin. Paradoxically, despite the impaired ability to fight viruses via the CTL pathway, patients do not suffer from severe viral infections, suggesting other immune mechanisms provide protection.
Viral and Cancer Evasion Tactics
The TAP transporter is a target for pathogens attempting to hide from the immune system. Many viruses have evolved strategies to sabotage its function. This is not a case of a genetically broken transporter, but a functional one being actively blocked. For example, herpes simplex virus (HSV) produces a protein called ICP47 that acts as a plug, physically blocking peptides from binding to TAP.
Other viruses employ different tactics. Human cytomegalovirus (HCMV) makes a protein, US6, that prevents the transporter from using the ATP it needs for energy. Adenoviruses and human papillomaviruses can reduce the amount of TAP1 protein the cell makes, limiting the number of functional transporters. These strategies all starve MHC Class I molecules of peptides, keeping infected cells hidden from Cytotoxic T Lymphocytes.
Cancer cells can adopt similar evasion tactics to avoid destruction. Rather than a viral protein inhibitor, some tumors reduce the expression of the TAP1 or TAP2 genes through a process called downregulation. By producing fewer TAP transporters, the cancer cell limits the number of abnormal cancer-related peptides that reach the cell surface. This diminished presentation makes it harder for the immune system to recognize and eliminate the malignant cells, contributing to tumor growth and survival.