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Questions and Answers
What is the primary event that leads to the greatest proliferative expansion of lymphocyte precursors in both B and T cells?
Which step is NOT part of the lymphocyte development process.
What types of B cells are identified during the differentiation process?
Which of the following is true regarding T cell differentiation?
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What term is used interchangeably with rearrangement in the context of antigen receptor development?
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What is the role of positive selection in T cell maturation?
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What type of MHC molecule do CD4+ T cells primarily interact with?
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Which process eliminates T cells that bind too strongly to self-antigens?
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What is a critical factor secreted by thymic stromal cells for T cell development?
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What primarily drives the movement of T cells into and through the thymus?
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Which event leads to apoptosis in developing T cells?
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What are the regions that specifically recognize antigens in the T cell receptor?
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What type of T cells mature into CD8+ T cells?
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Which transcription factors are primarily involved in B cell development?
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What is the role of IL-7 in T cell development?
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What is the relationship between DNA methylation and gene expression during lymphocyte development?
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Which gene deletion results in a loss of regulatory T cells in T lineage development?
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Which checkpoint is the first during lymphocyte development?
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What is the effect of epigenetic mechanisms on CD4 and CD8 T cell lineage commitment?
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Which of the following proteins are essential for both T and B cell development?
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What disorder is associated with mutations in the IL-7 gene?
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What is the role of pre-Tα in the formation of the pre-TCR complex?
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Which process allows thymocytes to survive and differentiate in response to weak binding with self peptide–MHC complexes?
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In which part of the thymus do functional and phenotypic differentiation of single-positive T cells occur?
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What type of T cells are formed from double-positive cells that successfully complete the selection processes?
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What is required for the proliferation and differentiation of naive T cells aside from antigen-induced signals?
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How does the interaction between CD40L on T cells and CD40 on APCs influence T cell responses?
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Which therapeutic approach utilizes costimulatory blockade to treat rheumatoid arthritis?
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Which type of T cell can differentiate into regulatory T cells (Treg CD4+) during thymocyte development?
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Study Notes
Lymphocyte Development
- Lymphocyte development or maturation is the process of differentiating lymphocyte progenitors in the thymus and bone marrow into mature lymphocytes that populate peripheral lymphoid tissues.
- During lymphocyte development, the greatest expansion of lymphocyte precursors occurs after successful rearrangement of the Ig heavy chain gene (B cell) or the TCR β chain gene (T cell)
- Commitment of progenitor cells to B lymphoid or T lymphoid lineage is part of lymphocyte development
- The process of lymphocyte development also includes the proliferation of progenitors and immature committed cells at specific stages, providing a large pool of cells that can generate useful lymphocytes.
- Lymphocyte development involves the sequential and ordered rearrangement of antigen receptor genes and the expression of antigen receptor proteins.
- Selection events that preserve cells that have produced functional antigen receptor proteins and eliminate potentially dangerous cells that strongly recognize self antigens are a key part of development.
- Lymphocyte development also includes the 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, natural killer T (NKT) cells, MAIT cells, and γδ T cells.
Regulation of Lymphocyte Development
- Epigenetic mechanisms that regulate lymphocyte development include methylation of DNA on certain cytosine residues, posttranslational modifications of the histone tails of nucleosomes, and active remodeling of chromatin by protein machines called remodeling complexes.
- Commitment of developing T cells to the CD4 or CD8 lineage depends on epigenetic mechanisms that silence the expression of the CD4 gene in CD8+ T cells.
- Silencing of gene expression by noncoding RNAs also contributes to the regulation. Deletion of Dicer, a key enzyme in miRNA generation, in the T lineage results in a preferential loss of regulatory T cells (Treg) and the consequent development of an autoimmune phenotype.
B and T Lymphocyte Repertoires
- The process of lymphocyte development contains numerous steps, called checkpoints.
- Pre-antigen receptors and antigen receptors deliver signals to developing lymphocytes that are required for their survival and for their proliferation and continued maturation.
- In the next step of maturation, developing B and T cells express complete antigen receptors. Cells are then selected for survival based on what these receptors recognize.
- Cells that express useful antigen receptors may be preserved, and potentially harmful cells that strongly recognize self structures may be eliminated.
- In the T cell lineage, positive selection ensures the maturation of T cells whose receptors recognize self major histocompatibility complex (MHC) molecules.
- Expression of the coreceptor on a T cell (CD8 or CD4) is matched to the recognition of the appropriate type of MHC molecule (class I MHC or class II MHC, respectively).
Checkpoints in Lymphocyte Maturation
- Positive selection preserves receptor-expressing cells and is coupled to the generation of different B cell subsets.
- Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens present in the generative lymphoid organs.
Stages of T Lymphocyte Maturation
- αβ T cells mature into CD4+ class II MHC–restricted, or CD8+ class I MHC–restricted T cells.
TCR Protein
- The TCR Protein contains variable domains and constant domains with CDRs (Complementary Determining regions)
Germline Organization of Human TCR
- TCR gene segments are rearranged to create a unique TCR receptor repertoire in each individual.
Human TCR Repertoire
- The human TCR repertoire is incredibly diverse, with billions of possible TCR combinations.
TCR Gene Recombination and Expression
- TCR genes undergo a process of recombination and expression, allowing for the generation of a diverse range of TCR receptors.
T Lymphocyte Maturation in the Thymus
- Thymic stromal cells secrete IL-7, a critical lymphopoietic growth factor.
- The movement of cells into and through the thymus is driven by chemokines, with CCR9: CCL25 in the cortex and CCR7: CCL19/21 in the medulla
- Cell death (Apoptosis) is due to failure to productively rearrange the TCR β chain gene, failure to be positively selected by self MHC molecules in the thymus, or self antigen–induced negative selection.
Pre-T Cell Receptor
- The TCR β chain is expressed on the cell surface in association with an invariant protein called pre-Tα, along with CD3 and ζ proteins to form the pre-TCR complex.
- TCR α gene expression in the double-positive stage leads to the formation of the complete αβ TCR.
- Double-positive cells that successfully undergo selection processes go on to mature into CD4+ or CD8+ T cells.
T Lymphocyte Subset in the Thymus
- Functional and phenotypic differentiation into CD4+CD8− or CD8+CD4− single-positive (SP) T cells occurs in the medulla of the thymus, and mature T cells are released into the circulation.
- Some double-positive cells differentiate into CD4+CD8− regulatory T cells (Treg CD4+).
- The selection of developing T cells is dependent on recognition of antigen (peptide–MHC complexes) in the thymus and is responsible for preserving useful cells and eliminating potentially harmful ones.
- Positive selection is the process where thymocytes whose TCRs bind with low avidity to self peptide–self MHC complexes are stimulated to survive and to differentiate either into CD4+ T cells or CD8+ T cells.
Activation of Naive and Effector T Cells by Antigen
- Naive and effector T cells are activated by antigen through a complex process that involves recognition of antigen presented by antigen-presenting cells (APCs).
Sequence of Events in T Cell Responses
- T cell responses involve a series of events, including antigen recognition, activation, clonal expansion, differentiation into effector T cells, and elimination of the antigen.
Role of Co-stimulation in T Cell Activation
- The proliferation and differentiation of naive T cells require signals provided by molecules on APCs, called costimulators, in addition to antigen-induced signals.
Costimulatory Pathways
- The interaction of CD40L on T cells with CD40 on APCs enhances T cell responses by activating the APCs.
Mechanisms of T Cell Costimulation by CD28
- CD28 is a key costimulatory molecule that promotes T cell activation by interacting with its ligands, CD80 (B7-1) and CD86 (B7-2), on APCs.
Costimulatory Molecules of the CD28 Family
- The CD28 family includes several costimulatory and coinhibitory molecules that regulate T cell activation and immune responses.
Therapeutic Costimulatory Blockade
- CTLA-4-Ig is an approved therapy for rheumatoid arthritis and transplant rejection. CTLA-4-Ig is an antibody that blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, thereby reducing T cell activation and preventing autoimmune disease.
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Description
This quiz covers the key processes involved in lymphocyte development, detailing the differentiation of lymphocyte progenitors in the thymus and bone marrow. It includes topics on gene rearrangement, commitment to lymphoid lineages, and the importance of selection events in ensuring functional antigen receptors. Test your understanding of these essential immunological concepts.
