Lymphocyte development
The Lymphocyte precursors originate in bone marrow. The Mature lymphocytes are present in variable proportions in the bone marrow: children less than 2 years of age may have up to 60%; adults usually have less than 20% but some develop lymphoid aggregates as they grow older. The terminal differentiation of mature lymphocytes takes place in secondary lymphoid organs after they leave the bone marrow. They Mature to B cells (humoral immune response) or T/NK cells (cell mediated immune response)B cells complete most of their development within the bone marrow, but T cells are generated in the thymus from precursor cells that migrate from the bone marrow
Recombination assembly of Ig and TCR genes represents the main process in the development of B and T cells (regulated by RAG-1, RAG-2 and TdT)
Initially children have B:T cell ratio of 2:1; after 4 to 5 years of age, proportion of B cells decreases and T cells increases, reaching adult levels during adolescence of the ratio 1:4 – 5
B cell maturation
B cell development in marrow is dependent on CD10 stromal cells, which form specific, adhesive contacts with developing B lineage cells and also provide growth factors (stem cell factor, IL7, stromal cell derived factor 1)
Earliest stem cells are in subendosteum, adjacent to inner bone surface; with maturation, B lineage cells move towards central axis of marrow; final stages of development of immature B cells occur in peripheral lymphoid organs which are spleen, lymph nodes
Germline B cells undergo a series of Ig gene rearrangements to produce a heavy chain (?) followed by light chains (? or ?). cytoplasmic CD22 appears to be the most specific B cell marker.A minor subset of B cells also express CD5 (T cell marker).Plasma cells are last stage of B cell maturation, express CD38 but lose CD19
T/NK cell maturation
T cells migrate from bone marrow to thymus and mature via TCR gene rearrangements
Most specific T cell marker is cytoplasmic CD3
During thymic maturation sequence, T cells are initially double negative for CD4 and CD8 (pro and prethymocytes), then double positive (cortical thymocytes), then express either CD4 or CD8 (medullary thymocytes)
In natural killer cells, rearrangements of T cell receptor genes do not occur; proportion of NK cells in bone marrow does not change with age
Unique developments that occur in lymphocyte development
Foreign antigens are recognized by receptors on B lymphocytes and T lymphocytes. BCRs and TCRs are heterodimers with each polypeptide chain composed of a C-terminal constant region and an N-terminal variable region that makes direct contact with antigen. The first two exons of all antigen receptor genes encode the variable region. The second exon is assembled in developing lymphocytes from component variable (V), joining (J), and, in some cases, diversity (D) gene segments through the process of V(D)J recombination, which requires the generation and repair of DNA double-strand breaks (DSBs). The assembly of different V, D, and J gene segments (combinatorial diversity) and the imprecision of the assembly process (junctional diversity) together provide the basis for the vast number of foreign antigens that the adaptive immune system is capable of recognizing. Moreover, successful assembly of the genes encoding the appropriate antigen receptor heterodimer is essential for normal B and T cell development. The BCR and TCR provide critical signals that support cell survival, proliferation, and maturation.
LYMPHOCYTE ANTIGEN RECEPTOR GENETIC DEVELOPMENT
It takes place in the following steps;
1 V(D)J recombination reaction
The V(D)J recombination reaction can be divided into a DNA cleavage step and a DNA joining step. This reaction is initiated when RAG-1 and RAG-2 (RAG endonuclease) introduce DNA DSBs at the border of two recombining gene segments and their flanking RAG recognition sequences recombination signals. This DNA cleavage results in the paired formation of broken DNA signal ends and coding ends that are joined forming a signal joint and coding joint. Recombination signals are composed of conserved heptamer and nonamer sequences separated by either 12 or 23 nonconserved base pairs. RAG cleavage occurs only in the setting of a synaptic complex that contains a pair of RSs of differing spacer lengths
2 Nonhomologous end-joining pathway in V(D)J recombination
DNA cleavage by the RAG proteins is restricted to the G1-phase of the cell cycle as RAG-2 is phosphorylated and degraded upon entry into the S-phase. RAG DSBs are repaired by the nonhomologous end-joining pathway of DNA DSB repair. RAG DSBs activate ataxia-telangiectasia mutated (ATM), which is also a member of the PI3K-like family of serine–threonine kinases. During the repair of RAG-mediated DSBs, ATM promotes the stability of coding ends in post cleavage complexes until they can be joined
3 The B lymphocyte antigen receptor genes
The B cell receptor , or immunoglobulin , is composed of two heavy (H) chains and two light (L) chains, either IgL? or IgL?. The second exon of the IgH gene is assembled from V, D, and J gene segments.
4 The Developmental regulation of IgH and IgL chain gene assembly
IgH chain gene rearrangement is initiated at the pro-B cell stage. Productive assembly of an IgH chain gene results in its expression in conjunction with the surrogate light chains (VpreB and ?5) as a pre-BCR. Signals from the pre-BCR lead to cessation of RAG expression, cellular proliferation, and transit to the pre-B cell developmental stage. The pre-BCR signals prevent additional VH to DJH rearrangements on the alternate allele by a process termed allelic exclusion. Pre-B cells must generate a productive IgL chain gene encoding an IgL chain that can pair with the IgH chain to generate a nonautoreactive mature BCR. IgL gene rearrangement is regulated by pre-BCR and cytokine signals that is interleukin-7, which control RAG expression and IgL locus accessibility
Conclusion
All developing lymphocytes generate many DNA DSBs as they attempt to assemble functional antigen receptor genes at different developmental stages. These DSBs activate canonical DNA damage responses that are required for the cellular response to these DSBs. However, recent studies have revealed that these physiologic DNA breaks also initiate a genetic program that is unique to and important for developing lymphocytes. In this regard, signals from RAG DSBs integrate with other important developmental signals, including those from the IL-7 and pre-BCR receptors, to direct lymphocyte maturation. These RAG DSB-dependent signals may directly regulate antigen receptor gene assembly by influencing allelic exclusion and the inter- and intraallelic ordering of the V(D)J recombination reaction or they may regulate processes that indirectly impact antigen receptor gene assembly, such as survival and proliferation of developing lymphocytes
References;
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654785/
www.pathologyoutlines.com/topic/bonemarrowlymphocytematuration
Amin RH, Schlissel MS. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nature Immunology. 2008;9:613–622. PMC free article PubMed
