T Cell Receptor Structure and Diversity

• Genes encoding alpha, beta, gamma, and delta T cell receptors (TCRs) are exclusively expressed in T cells.
• TCR genes (alpha, beta, gamma, delta) undergo rearrangement, similar to immunoglobulin genes, to expand antigen recognition.
• TCR gene clusters facilitate the effector functions of CD4+ and CD8+ T cells.
• Alpha-beta T cells are more common than gamma-delta T cells.

TCR Structure and Genetic Arrangement

• The TCR alpha chain, like the immunoglobulin light chain, is encoded by V, J, and C gene segments.
• The TCR beta chain, like the immunoglobulin heavy chain, is encoded by V, D, J, and C gene segments.
• TCR alpha chain rearrangement results in VJ joining.
• TCR beta chain rearrangement results in VDJ joining.

TCR Diversity Mechanisms

• Each T cell expresses unique antigen-specific TCRs with a single variable and constant region.
• TCR diversity enhances binding variability.
• The first level of diversity arises from DNA rearrangement in variable regions, with random V, D, and J gene selection.
• Random selection generates approximately 3 million different binding sites for alpha-beta chain TCRs.

VDJ Recombination Details

• Alpha chain genes are located on chromosome 14, and beta chain genes on chromosome 7.
• DNA is removed to join V and J genes in the alpha chain.
• For the beta chain, D genes are added to form the VDJ variable region, similar to heavy chains.
• VDJ rearrangement of TCRs for alpha-beta T cells leads to a large antigen-binding combination.
• TCR diversity generates a large repertoire of TCR binding sites, increasing the probability of ligand recognition and cell activation.

VDJ Recombination Components

• VDJ heavy chain gene recombination depends on recombination signal sequences (RSS) and RAG-1/RAG-2 recombinases.
• These components are also present in T cells, enabling VDJ recombination in TCR alpha and beta chains.

VDJ Recombination Advantage

• V, D, and J segments have different units (e.g., V1-Vn, D1-Dn, J1-Jn).
• Different combinations of V, D, and J segments can be combined during each recombination event to form a new type of TCR receptor.
• Although both T cells have alpha and beta chains, these chains differ slightly, resulting in differential affinity towards antigens, which is crucial for T cell responses.

Location of T Cell Rearrangements

• T cell development occurs in the thymus.
• T cells commit to their lineage in the cortical region, requiring Notch signaling.
• Committed T cells undergo double-negative stages.
• Beta chain rearrangement occurs during the transition from double-negative stage one to double-negative stage two.
• Alpha chain rearrangement occurs after double-negative stage four.
• Alpha-beta and gamma-delta rearrangements can occur, but gamma-delta rearrangement is extremely rare since two rearrangement events must happen already.

TCR Diversity Overview

• TCRs are essential for recognizing antigens presented by MHC molecules.
• TCR diversity is crucial for effective immune responses to various pathogens.
• The mechanisms of TCR diversity include gene rearrangement, combinatorial diversity, and junctional diversity.
• Genetic rearrangement of gene segments generates diversity, including kappa, lambda, V, D, and J segments.
• These segments can be combined, inverted, and modified through nucleotide deletion or alteration.
• Diversity also arises from combinations of variable and constant regions.

Mechanisms of TCR Diversity

• TCR genes undergo somatic recombination during T cell development in the thymus.
• Rearrangement of V, D, and J segments forms functional TCR genes encoding variable regions of TCR chains.
• Multiple V, D, and J gene segments exist, and their random recombination creates a vast number of combinations.
• Combinatorial diversity produces a pool of T cells each having a unique TCR with unique binding properties.

Function and Role of TCR Diversity

• TCRs recognize peptide antigens presented by MHC molecules on antigen-presenting cells (APCs).
• A diverse TCR repertoire ensures T cells can recognize a wide array of antigens.
• Each TCR is specific to a particular antigenic peptide-MHC complex, determined by the variable regions.
• TCR diversity allows adaptation and response to new or mutated pathogens.
• T cells’ ability to recognize a diverse set of antigens enhances the adaptive immune response's flexibility and effectiveness.

When TCR Diversity Occurs

• TCR diversity mechanisms occur in the thymus.
• Beta chain rearrangement occurs during the transition from the T1 to T2 double-negative stage.
• Alpha chain rearrangement occurs after the double-negative stage four.
• TCR diversity is established early in T cell development in the thymus.

Where TCR Diversity Occurs

• Gene rearrangement begins in the bone marrow during T cell progenitor development.
• T cell progenitors migrate to the thymus for further maturation and selection.
• Positive selection allows T cells with TCRs capable of recognizing self-MHC molecules to survive.
• Negative selection eliminates T cells with TCRs that strongly bind to self-antigens, preventing autoimmunity.
• The combination of these selection processes with TCR gene rearrangement ensures a diverse and functional T cell repertoire.