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Questions and Answers
What type of regulatory T cells do some double-positive cells differentiate into?
What is positive selection in T cell development primarily dependent on?
What role do costimulatory signals play in T cell activation?
What is the function of CD40L on T cells when it interacts with CD40 on APCs?
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Which therapy involves the blockade of CTLA-4 for treating rheumatoid arthritis?
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What is the first step in lymphocyte development after the commitment of progenitor cells?
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What role do transcription factors EBF, E2A, and Pax-5 play in lymphocyte development?
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What is the significance of IL-7 in T cell development?
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What type of selection occurs to preserve functional cells in lymphocyte development?
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Which of the following is NOT a subpopulation derived from T cells?
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What genetic mutations lead to X-linked severe combined immunodeficiency disease (X-SCID)?
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Which of the following describes the rearrangement and recombination of antigen receptor genes in lymphocyte development?
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What is the primary function of DNA methylation in lymphocyte development?
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What is the role of posttranslational modifications in histone tails?
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How do remodeling complexes influence gene expression?
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What happens when Dicer is deleted in the T lineage?
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What is the significance of the pre-antigen receptor in lymphocyte development?
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What is the result of positive selection in T cell maturation?
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How are mature T cells able to recognize foreign peptide antigens?
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What determines the lineage commitment of developing T cells?
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What common outcome results from recognizing self structures by T cells?
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What is the primary role of positive selection during lymphocyte maturation?
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What is a consequence of negative selection in lymphocyte maturation?
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Which domains are involved in the structure of the TCR protein?
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What critical factor is secreted by thymic stromal cells during T lymphocyte maturation?
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What initiates apoptosis during T lymphocyte maturation?
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During which stage is the complete αβ TCR formed?
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In what part of the thymus does functional differentiation into single-positive T cells occur?
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Which of the following processes occurs during the selection of T lymphocytes?
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Study Notes
Lymphocyte Development
- Lymphocyte development is the process by which lymphocyte progenitors in the thymus and bone marrow differentiate into mature lymphocytes
- The greatest proliferative expansion of lymphocyte precursors occurs after successfully rearranging 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
- 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.
- Selection events that preserve cells that have produced functional antigen receptor proteins and eliminate potentially dangerous cells that strongly recognize self antigens.
- Differentiation of B and T cells into functionally and phenotypically distinct subpopulations.
B cell development into subpopulations
- Follicular B cells
- Marginal zone B cells
- B-1 cells
T cell development into subpopulations
- CD4+ and CD8+ αβ T lymphocytes
- Natural killer T (NKT) cells
- MAIT cells
- γδ T cells
Transcription Factors and Signaling Proteins
- EBF, E2A, and Pax-5 transcription factors induce the expression of genes required for B cell development:
- Rag-1 and Rag-2 proteins
- Pre-B and the B cell receptor
- Downstream signaling proteins
- Notch 1 and GATA3 signaling proteins induce the expression of genes required for T cell development:
- Rag-1 and Rag-2 proteins
- IL-7 is required for the proliferation of T cell progenitors. Mutations in the IL-7 gene rise to an immunodeficiency disorder called X-linked severe combined immunodeficiency disease (X-SCID)
Epigenetic mechanisms that regulate Lymphocyte Development
- Methylation of DNA on certain cytosine residues that generally silences genes
- Posttranslational modifications of the histone tails of nucleosomes that may render genes either active or inactive depending on the histone modified and the nature of the modification
- Active remodeling of chromatin by protein machines called remodeling complexes that can also either enhance or suppress gene expression:
- 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: 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.
Selection Processes That Shape the B and T Lymphocyte Repertoires
- 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.
- The pre-antigen receptor is the first checkpoint during lymphocyte development
- Developing B and T cells express complete antigen receptors and the cells are 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
- The 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).
- Mature T cells whose precursors were positively selected by self MHC molecules in the thymus are able to 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 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
Domains of the TCR Protein
- Variable domains
- Constant domains
- CDRs: Complementary Determining regions
Germline Organization of Human TCR
- TCR α, β, γ, and δ genes are organized into several gene segments
- These segments include variable (V), diversity (D) (β and δ chains only), joining (J), and constant (C) gene segments.
Human TCR Repertoire
- The diversity of the TCR repertoire is generated by different combinations of V, D, and J gene segments.
TCR Gene Recombination and Expression
- The TCR α, β, γ, and δ genes undergo somatic recombination to generate a diverse repertoire of antigen 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:
- Cortex: CCR9:CCL25
- Medulla: CCR7:CCL19/21
- The cell death (Apoptosis) is due to a combination of factors, including:
- Failure to productively rearrange the TCR β chain gene and thus to fail the pre-TCR/β,
- 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 go on to mature into CD4+ or CD8+ T cells
T Lymphocytes 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+)
T cell Selection
- 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 in which thymocytes whose TCRs bind with low avidity (i.e., weakly) to self peptide–self MHC complexes are stimulated to survive and to differentiate either 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 the APCs.
Mechanisms of T cell costimulation by CD28
- CD28 on T cells interacts with B7-1 (CD80) and B7-2 (CD86) on APCs, leading to activation of PI3K and the MAPK pathways.
Costimulation molecules of the CD28 family
- CD28
- CTLA-4 (cytotoxic T lymphocyte-associated protein 4)
- ICOS (inducible costimulator)
- PD-1 (programmed death-1)
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. They work by preventing CTLA-4 or PD-1 from binding their ligands, reducing inhibition and enhancing T cell activation and enabling the cancer-bearing individual to mount more effective antitumor immune responses.
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Description
Explore the critical processes involved in the development of lymphocytes, including the differentiation of progenitor cells in the thymus and bone marrow. Dive into the genetics of B and T cell maturation, along with the selection events that ensure functionality and self-tolerance. This quiz will enhance your understanding of immunology and cell differentiation.
