B and t cells extra reading Flashcards
overview of lymphocyte development?
Overview of Lymphocyte Development
The maturation of B and T lymphocytes involves a series of events that occur in the primary (also called generative or central) lymphoid organs ( Fig. 8.1 ). These events include the following:
- Commitment of progenitor cells to the B lymphoid or T lymphoid lineage.
- Proliferation of progenitors and immature committed cells at specific early stages of development, providing a large pool of cells that can generate useful lymphocytes.
- The sequential and ordered rearrangement of antigen receptor genes and the expression of antigen receptor proteins. (The terms rearrangement and recombination are used interchangeably.)
- Selection events that preserve cells that have produced functional antigen receptor proteins and eliminate potentially dangerous cells that strongly recognize self antigens. These selection processes during development ensure that lymphocytes that express functional receptors with useful specificities will mature and enter the peripheral immune system.
- Differentiation of B and T cells into functionally and phenotypically distinct subpopulations. B cells develop into follicular, marginal zone, and B-1 cells, and T cells develop into CD4 + and CD8 + αβ T lymphocytes, γδ T cells, natural killer T (NKT) cells, and mucosa-associated invariant T (MAIT) cells. The properties and functions of these different lymphocyte populations are discussed in later chapters.
HSC?
Multipotent stem cells in the fetal liver and bone marrow, known as hematopoietic stem cells (HSCs), give rise to all lineages of blood cells, including lymphocytes (see Chapter 2 ) . HSCs mature into common lymphoid progenitors that can give rise to B cells, T cells, NK cells, and innate lymphoid cells ( Fig. 8.2 ). The maturation of B cells from progenitors committed to this lineage occurs before birth in the fetal liver and after birth in the bone marrow, with the final steps being completed in the spleen. Fetal liver–derived stem cells give rise mainly to a type of B cell called a B-1 cell, whereas bone marrow–derived HSCs give rise to the majority of circulating B cells (follicular B cells) and a subset of B cells called marginal zone B cells. Precursors of T lymphocytes emerge from the fetal liver before birth and from the bone marrow later in life and circulate to the thymus, where they complete their maturation. T cells that express γδ T cell receptors (TCRs) arise from fetal liver HSCs, and the majority of T cells, which express αβ TCRs, develop from bone marrow–derived HSCs. In general, the B and T cells that are generated early in fetal life have less diverse antigen receptors. Despite their different anatomic locations, the early maturation events of both B and T lymphocytes are fundamentally similar.
transcription factors for B cell development?
The EBF, E2A, and PAX5 transcription factors induce the expression of genes required for B cell development. These include genes encoding the RAG1 and RAG2 proteins, components of the pre-B cell receptor (pre-BCR), and proteins that contribute to signaling through the pre-BCR and the BCR.
checkpoint (1) in lymphocyte development?
Pre-antigen receptors and antigen receptors deliver signals to developing lymphocytes that are required for the survival of these cells and for their proliferation and continued maturation ( Fig. 8.3 ) . Pre-antigen receptors, called pre-BCRs in B cells and pre-TCRs in T cells, are signaling structures expressed during B and T cell development that contain only one of the two polypeptide chains present in a mature antigen receptor. Cells of the B lymphocyte lineage that successfully rearrange their Ig heavy chain genes express the μ heavy chain protein and assemble a pre-BCR. In an analogous fashion, developing T cells that make a successful TCR β chain gene rearrangement synthesize the TCR β chain protein and assemble a pre-TCR. The assembled pre-BCR and pre-TCR form complexes with proteins that generate signals for survival, proliferation, and the phenomenon of allelic exclusion (discussed later), and for the further development of B and T cells. Because of the random addition of nucleotides at junctions between segments of antigen receptor genes that are joined together during lymphocyte development and the triplet base pair code for determining amino acids, only about one in three antigen receptor gene rearrangements is in frame and, therefore, capable of generating a proper full-length protein. Such a successful rearrangement is sometimes called a productive rearrangement. If cells make out-of-frame or nonproductive gene rearrangements at the Ig μ or TCR β chain loci, the pre-antigen receptors are not expressed, the cells do not receive necessary survival signals, and they undergo programmed cell death. Thus, expression of the pre-antigen receptor is the first checkpoint during lymphocyte development.
negative selection?
Negative selection is the process that eliminates or alters developing lymphocytes whose antigen receptors bind strongly to self antigens present in the generative lymphoid organs. Developing B and T cells are susceptible to negative selection during a short period after antigen receptors are first expressed. Developing T cells with a high affinity for self antigens are eliminated by apoptosis, a phenomenon known as clonal deletion. Strongly self-reactive immature B cells may be induced to make further Ig gene rearrangements and thus avoid self reactivity. This phenomenon is called receptor editing. If editing fails, the self-reactive B cells die, which is also called clonal deletion. Negative selection of immature lymphocytes is an important mechanism for maintaining tolerance to many self antigens; this is also called central tolerance because it develops in the central (generative) lymphoid organs (see Chapter 15 ).
how does vdj begin?
Functional antigen receptor genes are created only in developing B and T lymphocytes after DNA rearrangement brings randomly chosen V, D (if present), and J gene segments into contiguity.
diff beetween bcr tcr genes
Key Differences Between B-cell Ig and T-cell TCR
Immunoglobulin (B cell):
Combines heavy and light chains (kappa or lambda).
Recognizes a wide range of antigens (proteins, carbohydrates, lipids, etc.).
Secreted as antibodies or displayed on the B-cell surface.
T-cell receptor (T cell):
Combines alpha and beta chains (or gamma and delta).
Recognizes peptides presented by MHC molecules.
The process of V(D)J recombination at any Ig or TCR locus involves the rearrangement of one V gene segment, one D segment (only in Ig heavy chain and TCR β and δ chain loci), and one J segment in each lymphocyte to form a single V(D)J exon that will code for the variable region of an antigen receptor protein ( Fig. 8.7 ) . In the Ig light chain and TCR α and γ loci, which lack D segments, a single rearrangement event joins a randomly selected V gene segment to a randomly selected J segment. The Ig H and TCR β and δ loci contain D segments, and at these loci two sequential rearrangement events are needed, first joining a D to a J and then a V segment to the fused DJ segment, with each segment type randomly selected from the inherited group of V, D, or J segment
RSS?
Lymphocyte-specific proteins that mediate V(D)J recombination recognize DNA sequences called recombination signal sequences (RSSs) that are located 3′ of each V gene segment, 5′ of each J segment, and flanking each side of every D segment ( Fig. 8.8A ) . The RSSs consist of a conserved stretch of 7 nucleotides, called the heptamer
During V(D)J recombination, double-strand breaks are generated between the heptamer of the RSS and the adjacent V, D, or J coding sequence. In Ig light chain V-to-J recombination, for example, breaks will be made 3′ of a V segment and 5′ of a J segment. The intervening DNA, containing signal ends (the ends that contain the heptamer and the rest of the RSS), is removed in the form of a circle, and the V and J coding ends are joined.
Review article: Luigi D. Notarangelo, MD
