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T Cells:Regulation and Cellular Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
However, the organization and rearrangement of Ig and TCR genes also have important differences: 1) TCR genes have fewer V region segments, and a greater number of J segments. 2) Junctional diversity with addition of N regions at gene segment junctions, and utilization of D genes in multiple reading frames, plays a greater role in generating diversity in the TCR repertoire. 3) TCR genes do not undergo somatic diversification following initial rearrangement. Expressed TCR genes are very stable during T cell development.
The Immunoglobulin Variable-Region Gene Repertoire and Its Analysis
Published in Cliburn Chan, Michael G. Hudgens, Shein-Chung Chow, Quantitative Methods for HIV/AIDS Research, 2017
Thomas B. Kepler, Kaitlin Sawatzki
In addition to combinatorial diversity, IgVRG exhibits junctional diversity. The enzymatic complex consisting of the recombination activating genes RAG1 and RAG2 binds to a recombination signal (RS) adjacent to each of the V, D, and J genes, bringing the genes into close proximity. Proper ordering of the genes is enforced by the so-called 12/23 rule. There are two different types of RS, one with a 12-nucleotide spacer and one with a 23-base spacer. Synapsis occurs only between heterogeneous pairs. The recombinase nicks the DNA at the start of each RS, resulting in a DNA hairpin on each gene, which is then cleaved stochastically by the Artemis complex, resulting in variable recombination points. Because of the hairpin structure, this cleavage may occur beyond the end of the coding region into the noncoding strand, resulting in the appearance of p-nucleotides (p for palindromic). Terminal deoxynucleotidyl transferase may then add several n-nucleotides (n for nontemplated), which are yet another source of stochasticity. The strands then pair in complementary regions, and unpaired nucleotides are removed and filled in to form the final junction region [19,25,26]. The site of RAG-mediated cleavage and n-nucleotides together supply the junctional diversity of the antibody repertoire.
The Inducible Defense System: The Induction and Development of the Inducible Defence
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael A. Hickey, Diane Wallace Taylor
The gene rearrangement process is similar in B and T cells. As shown in Figure 8.5, the first gene rearrangement that occurs randomly moves one D segment to join one of the J segments. This occurs first by a looping the DNA that brings the D and J regions into close proximity. Then the DNA between the D and J is cut out and the D and J segments are religated together. This process requires two enzymes called RAG1 and RAG2 (recombination-activating genes). Together RAG1 and RAG2 form a protein heterodimer which has a specific endonuclease activity. The interaction of the RAG1-RAG2 endonuclease with a recombinational signal sequence (RSS) catalyzes the breaking and joining of DNA needed for the DJ recombination. The intervening DNA forms a circle that is lost from the cells genome. During the cutting and splicing of the DNA, additional diversity is generated because DNA cutting and repair is not always precise. This imprecision leads to what as known as junctional diversity. To further increase the number of possible DNA sequences derived from the DJ rearrangement, nucleotides may be added to the ends of each newly cut DNA strand (Figure 8.5). This process is known as N-nucleotide addition and is mediated by the enzyme terminal deoxynucleotidyl transferase (TdT). Then, the D segment is ligated directly to the J segment, but the rejoined DNA may have gaps in one or both chains of the DNA. These gaps are then filled with palindromeic nucleotides through a process called P-nucleotide addition (Figure 8.5). This completes the DJ recombination. The same steps occur to join a random V gene segment to the newly rearranged DJ segment.
Expression and clinical significance of RAG1 in myelodysplastic syndromes
Published in Hematology, 2022
Xiaoke Huang, Xiaolin Liang, Shanhu Zhu, Qiongni Xie, Yibin Yao, Zeyan Shi, Zhenfang Liu
The plasticity of the acquired immune system in recognizing millions of possible antigens is largely due to the combinatorial joining of variable (V), diversity (D), and joining (J) gene segments that encode the antigen-binding regions of T cell receptors (TCRs) in T cells and B cell receptors (BCRs) in B cells, and the junctional diversity that can be introduced during the process of V(D)J recombination[5]. RAG1 and RAG2 proteins form a complex and initiate V(D)J recombination by introducing DNA double-strand breaks (DSBs) between the recombination signal sequences and the flanking V, D, or J gene segment. The human RAG1 protein consists of 1,043 amino acids, and the catalytic core (amino acids 387–1011) contains a nonamer-binding domain, a dimerization and DNA binding domain, a pre-RNase H and catalytic RNase H domain, 2 zinc-binding domains, and the carboxy-terminal domain, which are all crucial for V(D)J recombination[6, 7].
A perspective toward mass spectrometry-based de novo sequencing of endogenous antibodies
Published in mAbs, 2022
Sebastiaan C. de Graaf, Max Hoek, Sem Tamara, Albert J. R. Heck
Because there is an endless and constantly evolving pool of pathogens, the antibody repertoire needs to be incredibly diverse and versatile to counteract these challenges.24,25 In humans, this enormous diversity in the potential antibody repertoire is achieved through several mechanisms. Starting at the genomic level, the light and heavy chains are encoded in four genes each: Variable (V), Diversity (D), Joining (J), and Constant (C), with the light chain lacking the D-gene. These genes are encoded in multiple alleles, which can recombine to a staggering number of combinations (Figure 1b).26 The recombination process is also error-prone, leading to insertions and deletions at the junctions between the regions, referred to as junctional diversity. By recombination alone, the number of possible variable domain sequences already reaches tens of thousands. However, the eventual antibody diversity is expanded even further by natural polymorphisms, mutations, and class switching. As the major contributor to antibody hypervariability, somatic hypermutations can occur during B-cell affinity maturation and do so at a million-fold increased rate compared to the usual mutation rates.11 These mutations are largely concentrated in the complementarity-determining regions (CDR1-3), separated by framework regions (FR1-4), which form the conserved backbone of the Fab structure (Figure 1c). Located at the tips of the Y-shaped antibody structure, CDRs are primarily responsible for antigen binding, and, therefore, elucidation of their sequences is of the utmost importance for antibody discovery.
Immune repertoire: Revealing the “real-time” adaptive immune response in autoimmune diseases
Published in Autoimmunity, 2021
Meiyu Wu, Ming Zhao, Haijing Wu, Qianjin Lu
The (V), (J) and (C) segments constitute the BCR light chain or TCR alpha and gamma-chains, while an additional diversity (D) segment constitutes the BCR heavy chain or TCR beta and delta chains [18,19] (Figure 1(C)). The functional antigenic specificity of BCRs and TCRs is determined by three loops called complementarity-determining regions (CDRs). The single V gene segments encode CDR1 and CDR2 on both BCRs and TCRs, whereas the V, (D), and J segments encode CDR3 jointly (Figure 1(D)). It is not difficult to see that CDR3 plays the most critical role in conveying antigenic specificity. The RAG1 and RAG2 genes, two recombination activating genes [20,21], highly organize and mediate the recombination process, which creates another source of extreme diversity called junctional diversity. V, D and J gene segment rearrangement results in exonucleases mediating random deletions and with terminal deoxynucleotidyl transferase (TdT), mediating non-templated random insertions of N-nucleotides [22], leading to sequence diversification at the V-D, D-J, and V-J junctional regions (Figure 1(C)). For TCR, the possibilities of α/β chain pairing (Figure 1(C)) also play a significant role in diversifying the TCR repertoire, which has been estimated to cover a wide range of values (1011 to >1018) [23,24], depending on diversity calculations.