The adaptive immune system, specifically T cells, identifies and responds to foreign invaders or internal threats like cancer. T cells cannot directly recognize free-floating pathogens or toxins. Instead, they rely on antigen presentation, a complex communication system linking the innate and adaptive immune responses. This process involves specialized cells capturing, processing, and displaying fragments of foreign material—antigens—on their surface using Major Histocompatibility Complex (MHC) molecules. This system ensures the immune response is targeted.
The Primary Antigen-Presenting Cells
Antigen presentation is primarily orchestrated by professional Antigen-Presenting Cells (APCs). These cells include dendritic cells, macrophages, and B cells, each initiating T cell responses. Dendritic cells are the most potent initiators of T cell immunity, constantly sampling their environment. They acquire antigens through mechanisms like phagocytosis of large particles and macropinocytosis, the non-specific uptake of surrounding fluid.
Macrophages are highly efficient APCs, specializing in engulfing whole pathogens and cellular debris via phagocytosis. They process the internalized material and display the resulting antigenic peptides to T cells.
B cells use a specific method of antigen uptake. They employ their surface-bound B cell receptors (antibodies) to bind and internalize specific antigens through receptor-mediated endocytosis. This targeted mechanism allows B cells to concentrate a specific antigen, which they then process and present to T helper cells. Professional APCs are uniquely capable of activating T cells because they express specialized accessory molecules. They are distributed strategically throughout the body to ensure rapid detection of foreign presence and communication to the adaptive immune system.
The Internal Threat Mechanism (MHC Class I)
The Major Histocompatibility Complex Class I (MHC Class I) pathway alerts the immune system to threats originating from within the cell, such as viral infections or abnormal proteins. Almost all nucleated cells express MHC Class I molecules and participate in this surveillance. The process begins in the cytoplasm, where proteins destined for presentation are tagged with ubiquitin.
The tagged proteins are fed into the proteasome, which breaks them down into short peptide fragments, typically eight to ten amino acids long. These peptides are then transported from the cytoplasm into the endoplasmic reticulum (ER) by the Transporter Associated with Antigen Processing (TAP) complex.
The TAP complex actively moves the peptides across the ER membrane. Inside the ER, newly synthesized MHC Class I molecules are held by chaperone proteins like tapasin, which links the MHC molecule to the TAP transporter, forming a peptide-loading complex. A peptide fragment binds to the MHC Class I groove, stabilizing the complex.
Once loaded, the stable peptide-MHC Class I complex is transported through the Golgi apparatus to the cell surface. It is displayed for inspection by Cytotoxic T lymphocytes (CD8+ T cells), which recognize the MHC Class I molecule via their CD8 co-receptor. If the CD8+ T cell detects a foreign peptide, it identifies the cell as compromised and initiates cell death to eliminate the threat.
The External Threat Mechanism (MHC Class II)
The Major Histocompatibility Complex Class II (MHC Class II) pathway presents antigens acquired from the cell’s external environment. This mechanism is confined to professional APCs, which capture and process extracellular pathogens. The process starts when the APC engulfs the foreign material via endocytosis or phagocytosis, sealing the antigen within an intracellular vesicle.
As the endosome matures, it fuses with lysosomes, creating an acidic compartment where proteins are broken down into peptide fragments by hydrolytic enzymes. Simultaneously, MHC Class II molecules are synthesized in the endoplasmic reticulum and associate with the invariant chain (Ii). The invariant chain prevents premature peptide binding and directs the MHC Class II molecule toward the endosomal compartments.
During transport, the invariant chain is cleaved by proteases, leaving the Class II-associated Invariant chain Peptide (CLIP) lodged in the binding groove. A non-classical MHC molecule, HLA-DM, acts as a peptide-exchange catalyst. HLA-DM removes the CLIP fragment and helps the MHC Class II molecule bind to an antigenic peptide.
The loaded peptide-MHC Class II complex is transported to the cell surface. This signal is recognized by Helper T lymphocytes (CD4+ T cells), whose CD4 co-receptor binds to the MHC Class II molecule. Upon recognition of a foreign antigen, the CD4+ T cell activates and coordinates the broader immune response, such as activating B cells or enhancing macrophage function.
Signaling the Attack: The Immunological Synapse
The culmination of antigen presentation is the physical encounter between the APC and the T cell at the immunological synapse. This highly organized junction is where recognition and signaling molecules cluster, ensuring efficient communication. The formation of this synapse delivers the first of two necessary activation signals.
Signal 1: Antigen Recognition
Signal 1 is the antigen-specific interaction, delivered when the T cell Receptor (TCR) engages with the peptide fragment displayed within the MHC molecule groove. This initial recognition is necessary but insufficient for full activation; Signal 1 alone can lead to unresponsiveness (anergy). This mechanism prevents accidental activation by self-antigens and maintains immune tolerance.
Signal 2: Co-stimulation
To achieve full activation, the T cell requires a second, non-specific co-stimulatory signal (Signal 2). This signal is delivered through the interaction of molecules distinct from the MHC complex, primarily the CD28 receptor on the T cell binding to B7 family ligands (CD80 or CD86) on the APC. The presence of both Signal 1 and Signal 2 directs the T cell to proliferate, differentiate into effector cells, and launch a targeted immune response.
This two-signal requirement ensures T cells are only activated when they encounter a foreign antigen presented by an APC alerted by the innate immune system. Professional APCs upregulate B7 molecules only after encountering signs of danger. This ensures immune activation is specific and robust.