Week 7 - The Development of T Lymphocytes

The Development of T Lymphocytes

Introduction to T Cell Development

  • T cell development shares similarities with B cell development:

    • Both involve rearrangement processes.

    • Both types of cell undergo positive and negative feedback mechanisms.

  • T cells originate in the bone marrow and mature in the thymus.

  • Co-receptors involved in T cell functionality include CD4 and CD8.

T Cell Migration

  • T-cell precursors migrate from the bone marrow to the thymus for development.

  • Mature T cells exit the thymus and travel to secondary lymphoid tissues such as:

    • Spleen

    • Lymph nodes

    • Lung

    • Heart

    • GALT (Gut-Associated Lymphoid Tissue)

The Thymus

  • The thymus is a lymphoid organ located in the thorax above the heart.

  • It is comprised of two main regions:

    • Cortex

    • Medulla

  • Unique features include:

    • No lymphocyte recirculation; only maturation occurs here.

    • Immature T cells known as thymocytes interact with thymic stroma.

  • The thymus is completely developed at birth but begins to degenerate one year after birth.

Thymic Organization

  • Key structural components of the thymus:

    • Capsule: surrounds the organ

    • Trabeculae: internal support structure

    • Cortical epithelial cells and medullary epithelial cells derive from thymic origins.

    • Thymocytes are derived from bone marrow.

    • Hassall's corpuscles: structures identified in the medulla.

    • Dendritic cells and macrophages, both originating from bone marrow, contribute to the thymic function.

T Cell Production and Age-Related Changes

  • T cell production in the thymus varies by age, with % production depicted as follows:

    • Graph trend declining after the age of 25, approaching near 0% at age 50.

Developmental Stages of T Cells

T Cell Progenitors

  • T cell progenitors differ from mature T cells.

  • Interaction with stromal cells leads to division and differentiation, marked by the expression of T cell markers:

    • CD2 and CD5.

    • Double-negative thymocytes: lack expression of CD4 or CD8.

Rearrangement of T Cell Receptor Genes

  • Interleukin-7 (IL-7) and Notch signaling are critical for T cell development.

    • IL-7: secreted by stromal cells, important for T cell growth.

    • Notch: interacts with developing T cells, guiding maturation.

  • Gene expression changes include:

    • Double-negative lymphocytes begin to rearrange TCR (T-cell receptor) genes.

    • The receptor with the fastest rearrangement dominates TCR production.

Double-Negative to Double-Positive Transition

  • Transition from double-negative progenitors to double-positive thymocytes involves changes in receptor expression:

    • Rearrangement of α and β TCR genes.

    • Double-positive thymocytes express both CD4 and CD8 receptors.

    • Misarranged T cells undergo apoptosis, ensuring only correctly arranged TCRs survive.

Pre-T Cell Receptor

  • The pre-T cell receptor comprises a β-chain and a surrogate α-chain in complex with the CD3.

    • This forms a superdimer structure.

    • The α-chain is rearranged following successful β-chain assembly.

    • Compatibility of the α-chain with the β-chain is checked in the ER.

Selection Process in T Cell Development

Positive Selection

  • First selection phase during T cell development:

    • Ensures production of functional TCRs.

    • Validates TCR capability to recognize self-MHC molecules.

    • Only 2% of double-positive thymocytes survive through this phase.

    • Binding of MHC and TCR triggers thymocyte survival and maturation.

  • Positive selection determines if T cells become CD4 or CD8:

    • CD8 T cells form if there’s binding with MHC class I.

    • CD4 T cells form if there’s binding with MHC class II.

Negative Selection

  • Negative selection eliminates self-reactive T cells:

    • It deletes cells with TCRs that bind too tightly to self-peptides and self-MHC complexes.

    • This process is crucial for preventing autoimmune responses and is mediated by dendritic cells and macrophages.

Final T Cell Maturation and Functions

  • Mature T cells circulate throughout the body for several years until encountering specific antigens.

  • Upon antigen encounter, they divide and differentiate into effector T cells:

    • CD8 T cells differentiate into cytotoxic T cells.

    • CD4 T cells differentiate into helper T cells.

Conclusion

  • Once matured and functioning, T cells engage actively in the immune response, reinforcing their role as pivotal components of adaptive immunity.