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Questions and Answers
What is the primary function of positive selection in T cell development?
Which molecules on antigen-presenting cells (APCs) are essential for the activation of naive T cells?
What role does CD40L play in T cell activation?
What is CTLA-4-Ig primarily used for in therapeutic settings?
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What effect do antibodies blocking CTLA-4 and PD-1 have on T cell responses?
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What is the initial step in lymphocyte development?
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What happens after the Ig heavy chain gene or TCR β chain gene is successfully rearranged?
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Which transcription factors are crucial for B cell development?
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What is the role of IL-7 in T cell development?
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Which type of cell develops into CD4+ and CD8+ αβ T lymphocytes?
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What does the process of selection in lymphocyte development achieve?
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What is a known effect of mutations in the IL-7 gene?
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What is the primary effect of DNA methylation in lymphocyte development?
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What type of modifications can affect gene activity in histone tails?
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What is the role of remodeling complexes in chromatin?
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What happens to the CD4 gene in CD8+ T cells during development?
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What is the function of Dicer in T cell development?
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What occurs during positive selection in T cell development?
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Which receptors play a critical role in lymphocyte survival and maturation?
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What can occur if regulatory T cells (Treg) are lost due to Dicer deletion?
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What is the first checkpoint during lymphocyte development?
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How does antigen receptor expression influence developing B and T cells?
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What is the ultimate recognition capability of mature T cells derived from positive selection?
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What is the primary purpose of positive selection in lymphocyte maturation?
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Which process leads to the elimination of lymphocytes that bind too strongly to self-antigens?
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In the maturation of αβ T cells, what do CD4+ T cells primarily respond to?
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What role does IL-7 play in T lymphocyte maturation?
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What triggers the apoptosis of thymocytes during T cell maturation?
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What is formed when the TCR β chain is expressed in association with pre-Tα?
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Where does functional differentiation occur in T lymphocyte maturation?
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Which cells are produced during the completion of T lymphocyte maturation?
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What is the main function of chemokines in T lymphocyte maturation?
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Which complex is formed once TCR α gene expression occurs in the double-positive stage?
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Study Notes
Lymphocyte Development
- Lymphocytes develop through a process called lymphocyte maturation or lymphocyte development.
- Proliferation of lymphocyte precursors is at its highest after the successful rearrangement of the Ig heavy chain gene (B cell) or the TCR β chain gene (T cell)
- Commitment of progenitor cells to the B lymphoid or T lymphoid lineage is a key stage in development.
- Proliferation of progenitors and immature committed cells is essential to create a pool of cells that can generate functional lymphocytes.
- Lymphocyte development involves the sequential rearrangement of antigen receptor genes and the expression of antigen receptor proteins.
- Selection events are crucial to preserve cells with functional antigen receptors, while eliminating cells that recognize self-antigens.
- B cells can differentiate into follicular, marginal zone, and B-1 cells.
- T cells differentiate into CD4+ and CD8+ αβ T lymphocytes, NKT cells, MAIT cells, and γδ T cells.
T Lymphocyte Development
- EBF, E2A, and Pax-5 transcription factors induce the expression of genes essential for B cell development.
- These factors regulate the expression of Rag-1 and Rag-2 proteins, pre-B cell receptor components, and downstream signaling proteins.
- Notch 1 and GATA3 signaling proteins induce the expression of genes required for T cell development. Including Rag-1 and Rag-2 proteins.
- IL-7 is crucial for the proliferation of T cell progenitors. Mutations in the IL-7 gene can lead to X-linked severe combined immunodeficiency disease (X-SCID).
Epigenetic Regulation of Lymphocyte Development
- Methylation of DNA on cytosine residues often silences genes.
- Posttranslational modifications like acetylation, methylation, and ubiquitination of histone tails in nucleosomes can activate or inactivate genes.
- Chromatin remodeling complexes can enhance or suppress gene expression.
- For example, the commitment of developing T cells to the CD4 or CD8 lineage relies on epigenetic mechanisms that silence the expression of the CD4 gene in CD8+ T cells.
- Silencing of gene expression by noncoding RNAs plays a role in T cell development.
- Deletion of Dicer, a key enzyme in miRNA generation, in the T lineage can lead to a loss of regulatory T cells (Treg) and potentially autoimmune phenotypes.
Selection Processes in B and T Lymphocyte Development
- Lymphocyte development involves checkpoints during the maturation process.
- Pre-antigen receptors and antigen receptors deliver signals to developing lymphocytes that are essential for their survival, proliferation, and continued maturation.
- The pre-antigen receptor is the first checkpoint in lymphocyte development.
- Cells express complete antigen receptors in the next stage of B and T cell maturation. Survival of these cells is determined by their antigen receptor recognition.
- Cells that express useful antigen receptors are preserved, while potentially harmful cells that strongly recognize self-structures are eliminated.
- Positive selection ensures the maturation of T cells whose receptors recognize self major histocompatibility complex (MHC) molecules.
- The expression of the coreceptor on a T cell (CD8 or CD4) is matched to the recognition of the appropriate MHC molecule (class I MHC or class II MHC).
- Mature T cells, whose precursors were positively selected by self MHC molecules in the thymus, can recognize foreign peptide antigens displayed by the same self MHC molecules on antigen-presenting cells in peripheral tissues.
Checkpoints in Lymphocyte Maturation
- Positive selection preserves receptor-expressing cells and contributes to the generation of different B cell subsets.
- Negative selection eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens 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 Domains
- The TCR protein has variable domains and constant domains.
- Complementary determining regions (CDRs) in the variable domains play a critical role in antigen recognition.
Germline Organization of Human TCR
- The human TCR genes are located on chromosomes 7, 14, and 15. Each TCR gene is comprised of variable (V), diversity (D), joining (J), and constant (C) gene segments.
- The TCR beta chain gene is assembled first.
Human TCR Repertoire
- The TCR repertoire encompasses a vast diversity of TCRs, enabling recognition of a wide range of antigens.
TCR Gene Recombination and Expression
- Rearrangement of TCR genes during T cell development leads to the generation of unique TCRs.
T Lymphocyte Maturation in the Thymus
- Thymic stromal cells secrete IL-7, a critical lymphopoietic growth factor.
- Chemokines drive the movement of cells into and through the thymus.
- Cortex: CCR9:CCL25
- Medulla: CCR7:CCL19/21
- Cell death during thymocyte development can happen due to:
- Failure to productively rearrange the TCR β chain gene and fail the pre-TCR/β checkpoint
- Failure to be positively selected by self-MHC molecules in the thymus
- 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 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. Mature T cells are then released into circulation.
- Some double-positive cells differentiate into CD4+CD8− regulatory T cells (Treg CD4+).
T Cell Selection
- The selection of developing T cells relies on the recognition of antigen (peptide–MHC complexes) in the thymus. This process ensures the preservation of useful cells and the elimination of potentially harmful ones.
- Positive selection occurs when thymocytes whose TCRs bind with low avidity (weakly) to self peptide–self MHC complexes are stimulated to survive and differentiate into CD4+ T cells or CD8+ T cells.
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 APCs.
Mechanisms of T Cell Costimulation by CD28
- CD28 provides an important costimulatory signal for T cell activation.
Costimulatory Molecules of the CD28 Family
- The CD28 family includes costimulatory receptors that play a role in T cell activation and regulation.
Therapeutic Costimulatory Blockade
- CTLA-4-Ig is an approved therapy for rheumatoid arthritis and transplant rejection.
- Inhibitors of the CD40L:CD40 pathway are in clinical trials for transplant rejection and autoimmune diseases.
- Antibodies that block the CTLA-4 and PD-1 inhibitory receptors are approved for the immunotherapy of tumors. Blocking these pathways enhances T cell activation and can improve antitumor immune responses.
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Description
Test your knowledge on the process of lymphocyte development, including the stages of maturation and differentiation of B and T cells. This quiz covers key concepts such as gene rearrangement, selection events, and the various types of lymphocytes. Dive in to see how well you understand this vital aspect of immunology!
