Antigen presentation is a fundamental mechanism that allows the immune system to recognize and respond to potential threats. It acts as the bridge between the non-specific innate immune system and the targeted adaptive immune system. This process involves displaying small fragments of a foreign substance, known as an antigen, on the surface of a cell. Specialized immune cells, called T-cells, cannot directly detect an intact pathogen. Instead, T-cells rely on the precise presentation of these processed molecular pieces to confirm danger, triggering a powerful immune reaction.
Key Players: Antigen Presenting Cells and MHC Molecules
Antigen presentation relies on specialized immune cells and surface display structures. Certain immune cells capture, internalize, and process foreign material, earning them the designation of Antigen Presenting Cells (APCs). Professional APCs include dendritic cells, macrophages, and B cells, which patrol tissues for signs of infection. Dendritic cells are considered the most potent, gathering antigens and traveling to lymph nodes to initiate T-cell responses.
The second component is the Major Histocompatibility Complex (MHC), a group of protein molecules on the cell surface. These molecules act as display platforms that hold processed antigen fragments for T-cell inspection. In humans, they are called Human Leukocyte Antigens (HLA). MHC molecules are highly polymorphic, meaning they vary significantly between individuals, allowing them to bind and present a wide range of different peptides.
There are two main classes of MHC molecules, Class I and Class II, designed to present antigens from different cellular locations. MHC Class I molecules are expressed on nearly all nucleated cells, allowing every cell to signal its internal state. MHC Class II molecules are restricted to professional APCs like dendritic cells and macrophages. This distinction dictates which T-cells recognize the presented antigen and determines the resulting immune response.
Processing and Presentation of Extracellular Threats (MHC Class II Pathway)
The MHC Class II pathway handles threats originating outside the cell, such as bacteria, fungi, or toxins. The mechanism begins when a professional APC, like a macrophage or dendritic cell, engulfs the foreign material through phagocytosis or endocytosis. The internalized pathogen is contained within a membrane-bound compartment called a phagosome or endosome.
The phagosome fuses with lysosomes, creating an acidic environment where specialized enzymes break down large foreign proteins into smaller peptide fragments. Meanwhile, MHC Class II molecules are synthesized in the endoplasmic reticulum (ER) and associated with the invariant chain (Ii). The Ii prevents premature peptide binding within the ER and guides the MHC Class II molecule toward the endosomal pathway.
As the MHC Class II molecule moves, the invariant chain is degraded, leaving the Class II-associated Invariant chain Peptide (CLIP) lodged in the binding groove. The CLIP fragment is removed and exchanged for the antigenic peptide generated from the engulfed pathogen. This exchange is catalyzed by the non-classical MHC molecule HLA-DM. The stable MHC Class II-peptide complex is then transported to the cell surface, where it is presented exclusively to CD4+ T-cells, also known as Helper T-cells.
Processing and Presentation of Intracellular Threats (MHC Class I Pathway)
The MHC Class I pathway monitors the internal environment of a cell, targeting threats that replicate inside the cytoplasm, such as viruses or abnormal proteins in cancer cells. Since almost all nucleated cells express MHC Class I, this mechanism surveys nearly every cell for internal infection. The process begins with the degradation of internal proteins, both normal and foreign, into short peptide fragments.
This protein breakdown is carried out by the proteasome, a large multi-protein complex located in the cytoplasm. If the cell is infected, viral proteins are also targeted for degradation. The resulting peptides are then transported from the cytoplasm into the endoplasmic reticulum (ER) lumen via the specialized protein complex called the Transporter associated with Antigen Processing (TAP).
Inside the ER, newly synthesized MHC Class I molecules are assembled and held in place by chaperone proteins, such as tapasin, forming a complex with TAP. Peptides entering the ER are loaded onto the binding groove of the MHC Class I molecule. Once successfully bound, the MHC Class I-peptide complex stabilizes and is released from the ER. The stable complex is then transported to the cell surface for presentation to CD8+ T-cells, also known as Cytotoxic T-cells.
Activating the Adaptive Immune System
The final step in antigen presentation is the physical encounter between the antigen-presenting cell and a T-cell, which activates the adaptive immune response. T-cells use the T-cell Receptor (TCR) to scrutinize the MHC-peptide complexes displayed on the cell surface. The TCR is highly specific and only recognizes a particular foreign peptide bound to a specific MHC molecule.
If a Helper T-cell (CD4+) recognizes a foreign peptide presented by MHC Class II, it becomes activated. The activated Helper T-cell multiplies rapidly and releases signaling molecules called cytokines. These cytokines coordinate the broader immune response by stimulating other cells, such as B cells to produce antibodies and macrophages to enhance their killing ability.
Conversely, if a Cytotoxic T-cell (CD8+) recognizes a foreign peptide presented by MHC Class I, it is activated. The activated CD8+ T-cell becomes a killer cell. Its function is to locate and destroy any cell displaying that specific MHC Class I-peptide complex, eliminating virus-infected cells or cancer cells.