The Development of T Lymphocytes

7-1: The Development of T Cells in the Thymus

  • Thymus as a Primary Lymphoid Organ:

    • The thymus is involved in T cell development but not in direct immune response to infection.

    • Composed mainly of thymocytes (immature T cells), macrophages, dendritic cells, and thymic stroma (epithelial cells).

7-2: Thymocyte Lineage Commitment

  • Cell Migration:

    • Progenitor stem cells enter the thymus before rearranging T-cell receptor (TCR) genes.

    • Stem cells begin acquiring receptors, adhesion molecules, and signaling molecules like IL-7.

  • Thymocyte Characteristics:

    • Double-negative (DN) thymocytes lack markers CD4, CD8, CD3, and TCR but have T cell characteristics.

7-3: Lineage Differentiation of T Cells

  • Thymocyte Progenitor Cell:

    • Double Negative thymocytes initiate TCR gene rearrangement, entering a "race" to become αβ or γδ T cells.

    • If the γ or δ genes rearrange first, a γδ T cell forms; if the β gene rearranges first, it may form an αβ T cell.

  • Double Positive (DP) Thymocytes:

    • Express both CD4 and CD8 after successful β chain rearrangement, forming a pre-TCR that anchors the β chain.

  • Apoptosis of Non-Functional TCR:

    • Cells with non-functional TCRs undergo apoptosis, and macrophages clear dead cells.

7-4: Gene Rearrangement in DN Thymocytes

  • Rearrangement Process:

    • Genes for β, γ, and δ chains undergo rearrangement in DN thymocytes.

  • Pre-T Cell Receptor (pre-TCR):

    • Successful β-chain rearrangement leads to pre-TCR formation, which signals the cell to proliferate and mature.

7-5: α-Chain Gene Rearrangement in Pre-T Cells

  • Rearrangement Characteristics:

    • The α-chain gene rearrangement occurs only in pre-T cells and lacks a D segment, favoring successful adjustments.

    • When the α-chain is rearranged, the δ locus is excised, preventing the development of γδ T cells.

7-6: Developmental Stages of T Cells Marked by Gene Expression Changes

  • Early Development:

    • T cell development is marked by checkpoints such as pre-TCR formation and α-chain gene rearrangement.

7-7: Positive Selection of T Cells in the Thymus

  • Positive Selection:

    • Thymocytes recognizing self-MHC undergo positive selection influenced by thymic epithelial cells presenting self-peptide-MHC complexes.

  • Selection Measurement:

    • Effective binding leads thymocytes to survive; weak or absent binding results in apoptosis.

7-8: Impact of Thymic Specific Proteasome on Positive Selection

  • Peptides Importance:

    • Thymic specific proteasome generates peptides that influence positive selection, ensuring T cells that moderate self-reactivity survive.

7-9: Continuing α-Chain Rearrangement

  • Receptor Editing:

    • Defines the adaptation process by which T cells alter their α-chains to enhance binding to self-MHC, occurring during positive selection.

7-10: CD4 vs CD8 T Cell Precursor Decision

  • Selection Mechanism:

    • Interaction of TCR with peptide-MHC determines the lineage commitment to either CD4 or CD8 T cell.

    • DP thymocytes lose expression of one co-receptor (CD4 or CD8), becoming single-positive T cells.

7-11: Negative Selection of Self-Reactive T Cells

  • Neglect in Thymus:

    • Thymic dendritic cells and macrophages present self-antigens.

    • Strongly binding TCRs signal apoptotic pathways to eliminate potentially autoreactive T cells.

7-12: Role of AIRE in Negative Selection

  • Expression of Tissue-Specific Proteins:

    • The autoimmune regulator (AIRE) drives expression of non-thymic proteins, ensuring elimination of self-reactive T cells.

  • Pathology Involvement:

    • AIRE deficiency leads to autoimmune diseases such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), reflecting increased self-reactive T cell survival.

7-13: Regulatory CD4 T Cells and Lineage

  • Regulatory Function:

    • Regulatory T cells (Tregs) maintain tolerance against self-antigens, providing additional control beyond negative selection.

    • Mechanism of selection for Tregs remains unclear.

7-14: Post-Thymic T Cell Differentiation in Secondary Lymphoid Tissue

  • After the Thymus:

    • T cells circulate between blood, lymph, and secondary lymphoid organs, remaining long-lived.

    • Upon antigen recognition, T cells differentiate into various effector subtypes (e.g., TH1 and TH2).

Chapter Overview and Therapy Implications

  • Therapeutic Relevance:

    • Bone marrow transplants require HLA compatibility to avoid graft versus host disease (GVHD).

    • Organ rejection occurs when the recipient immune system targets transplanted tissue due to HLA mismatch.

    • Immunotherapy seeks to utilize T cell capabilities for tumor eradication.