The human immune system constantly works to protect the body from a vast array of disease-causing invaders like bacteria, viruses, fungi, and parasites. It must also distinguish between these harmful external threats and the body’s own healthy tissues. This protective function presents a significant challenge: how can a limited set of genetic information prepare for potentially millions of different pathogens the body might encounter throughout a lifetime? VDJ recombination is a biological process that helps the immune system meet this challenge. It enables the creation of diverse recognition tools necessary for a robust defense.
Building a Diverse Immune System
The immune system’s ability to recognize and respond to foreign substances relies on the diversity of its antigen receptors. These unique receptors are found on specialized immune cells called B cells and T cells. B cells produce antibodies, which serve as their receptors, while T cells have T-cell receptors (TCRs). VDJ recombination generates this immense variety from a relatively limited set of inherited genetic material.
The Genetic Assembly Line
VDJ recombination is a complex genetic rearrangement that occurs during the development of B cells in the bone marrow and T cells in the thymus. This process involves the selective joining of different gene segments: Variable (V), Diversity (D), and Joining (J) segments. For instance, in the heavy chain of antibodies and the beta chain of T-cell receptors, a D segment first joins with a J segment. Subsequently, a V segment combines with this newly formed DJ complex, creating a VDJ gene segment. Light chains of antibodies and alpha chains of T-cell receptors undergo a similar VJ recombination, as they lack D segments.
Specialized enzymes, particularly Recombination Activating Genes 1 and 2 (RAG1 and RAG2), initiate this process by recognizing specific DNA sequences called recombination signal sequences (RSSs) that flank the V, D, and J segments. RAG enzymes create precise cuts in the DNA at these signal sequences, generating double-strand breaks. After RAG creates these breaks, cellular DNA repair machinery, specifically the non-homologous end joining (NHEJ) pathway, joins the DNA segments together.
Further diversity is introduced at the junctions where these segments are joined. An enzyme called terminal deoxynucleotidyl transferase (TdT) can randomly add extra nucleotides (N-nucleotides) to these cut ends before they are ligated. This random addition, along with the imprecise joining of the cut ends, significantly expands the potential combinations of V, D, and J segments. The intervening DNA segments between the chosen V, D, and J segments are typically excised and lost during this process.
Immunity Through Recognition
The direct outcome of VDJ recombination is the creation of highly diverse antigen receptors on B and T cells. Once formed, these unique receptors are displayed on the cell surface, ready to specifically recognize and bind to foreign invaders, or antigens. For B cells, the binding of an antigen to its specific antibody receptor activates the B cell. This activation can lead to the B cell differentiating into plasma cells that produce large quantities of soluble antibodies, which then target the pathogen for destruction.
Similarly, T cells use their rearranged T-cell receptors to recognize fragments of antigens presented on the surface of other cells, often infected cells or antigen-presenting cells. This specific recognition triggers the T cell to initiate various defensive actions, such as directly killing infected cells or coordinating other immune cells through chemical signals. The immense diversity generated by VDJ recombination ensures a targeted and effective immune response against a wide range of threats.
When Recombination Goes Wrong
Despite the precision of VDJ recombination, malfunctions can occur, leading to serious consequences for immune health. One such condition is severe combined immunodeficiency (SCID), where defects in the recombination machinery, particularly in RAG genes, result in a severe lack of functional B and T cells. Individuals with SCID are highly susceptible to infections.
In rare instances, errors during VDJ recombination can also lead to unintended chromosomal translocations. This occurs when the DNA cutting and rejoining process goes awry, causing segments of chromosomes to break and rejoin incorrectly with other chromosomes. Such errors can activate oncogenes, genes that can cause cancer. These chromosomal translocations are associated with the development of certain blood cancers, including lymphomas and leukemias. The precise regulation of VDJ recombination is important for preventing these detrimental outcomes.