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.
T cell-independent antigens + t cell dependent vs independent?
Multivalent antigens with repeating determinants, such as polysaccharides, can activate B cells without T cell help. Most T-independent antigens, such as polysaccharides, contain multiple identical epitopes on each molecule. Such multivalent antigens can effectively cross-link many B cell antigen receptors and initiate responses even though they are not recognized by helper T lymphocytes.
T-independent responses are rapid but relatively simple, consisting mostly of low-affinity IgM antibodies, whereas T-dependent responses are slower to develop but result in more durable, high-affinity antibodies that are typically of the IgG, IgA, or IgE isotypes.
Neutrophil AND B CELL LINK?
. Myeloid cells activated by TLRs may secrete APRIL (a proliferation-inducing ligand) and BAFF (B cell–activating factor), cytokines that can promote T-independent B cell response
Effects of B Cell Antigen Receptor Engagement on B Cells
Phenotypic Change Functional Consequence
Increased expression of CCR7: Migration toward T cell zone
Increased expression of B7 costimulators: Enhanced ability to activate helper T cells
Increased expression of receptors for T-cell cytokines :Increased responsiveness to signals from helper T cells
Increased expression of anti-apoptotic proteins: Increased survival of B cells
this is for the t-dependent pathway
These changes may be induced by binding of protein antigens to the B cell receptor, and they prepare B cells to respond to T cell help. Protein antigens are also internalized, processed, and presented to helper T cells.
first step of t cell dependent response?
The Sequence of Events During T Cell–Dependent Antibody Responses
Protein antigens are independently recognized by specific B and T lymphocytes in secondary lymphoid organs, and the two activated cell types interact with each other to initiate humoral immune responses ( Fig. 12.6 ) . Naive CD4 + T cells are activated in the T cell zones by antigen (in the form of processed, MHC-associated peptides) presented by DCs. Naive B cells in the follicles are activated by the same antigen (in its native conformation) that is transported there. The activated helper T cells and activated B cells migrate toward one another and interact at the edges of the follicles, where the initial antibody response develops. Some of the activated T and B cells migrate into follicles to form germinal centers, where more specialized antibody responses are induced. Next we will describe each of these steps in detail.
Role of CD40L:CD40 Interaction in T-Dependent B Cell Activation
Upon activation, helper T cells express CD40 ligand (CD40L), which engages its receptor, CD40, on antigen-stimulated B cells and induces B cell proliferation and differentiation, initially in extrafollicular foci and later in germinal centers ( Fig. 12.9 ) . CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily (see Chapter 10 ). Its ligand, CD40L (CD154), is a trimeric membrane protein that is homologous to TNF. CD40 is constitutively expressed on B cells, and CD40L is expressed on the surface of helper T cells that have been recently activated by antigen and costimulators. When these activated helper T cells interact physically with antigen-presenting B cells, CD40L binds to CD40 on the B cell surface. This results in conformational alteration of preformed CD40 trimers, which induces the association of cytosolic proteins called TNF receptor–associated factors (TRAFs) with the cytoplasmic domain of CD40. The TRAFs recruited to CD40 initiate enzyme cascades that lead to the activation and nuclear translocation of transcription factors, including NF-κB (nuclear factor κB) and AP1 (activator protein 1), which collectively stimulate B cell proliferation and increased synthesis and secretion of Ig. Similar signaling pathways are activated by TNF receptors (see Chapter 7 ). CD40-induced signals are also crucial for subsequent germinal center reactions, as we will discuss later. In addition, T cell–mediated DC and macrophage activation involves the interaction of CD40L on activated helper T cells with CD40 on DCs and macrophages
how does germinal centre form.
B cells that are activated by helper T cells through CD40L in the extrafollicular foci undergo isotype switching. In fact, extracellular foci are the site at which most isotype switching occurs during antibody responses to protein antigens. The antibody-secreting cells that are generated in extrafollicular foci, including plasmablasts and tissue plasma cells, are mostly short-lived, and these cells do not acquire the ability to migrate to distant sites, such as the bone marrow. In secondary lymphoid organs, plasmablasts downregulate CXCR5 and CCR7, upregulate CXCR4, and migrate into the red pulp (in the spleen) or medullary cords (in lymph nodes) in response to the CXCR4 ligand CXCL12. Rather than taking on plasmablast properties, some of the B cells activated at the follicle–T zone interface become precursors of germinal center B cells. FDCs release CXCL13, which draws in small numbers (a few to 100) of such cells. These precursor cells downregulate EBI2 and upregulate receptors that promote their confinement to the follicle center and initiate the germinal center reaction. The extrafollicular response also helps to generate T follicular helper (Tfh) cells that migrate into the follicle and are required for germinal center formation.
Germinal centers develop in secondary lymphoid organs approximately 4 to 7 days after the initiation of a T-dependent B cell response
what are tfh and when do they form?
Within 4 to 7 days after antigen exposure, activated antigen-specific B cells outside the follicle induce some previously activated T cells to differentiate into Tfh cells, which express high levels of the chemokine receptor CXCR5, are drawn into lymphoid follicles by CXCL13, the ligand for CXCR5, and play critical roles in germinal center formation and function. In addition to CXCR5, Tfh cells express ICOS (inducible costimulator), PD-1 (programmed cell death protein-1), the cytokine interleukin-21 (IL-21), and the transcription factor BCL-6. Tfh cells have a phenotype that makes them distinct from the Th1, Th2, and Th17 subsets of effector T cells described in Chapter 10 .
