Lecture 10 Notes: Development of T-Lymphocytes

Overview of T Cell Development

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

  • Mature T cells exit the thymus to secondary lymphoid tissues (e.g., spleen, lymph nodes).

Thymic Microenvironment

  • Thymic Stroma:

    • Composed of epithelial cells, dendritic cells (DCs), and macrophages.

    • Provides a specialized microenvironment crucial for T cell maturation.

Thymocyte Development Stages

  • Double-negative Thymocytes (DN):

    • Lack CD4 and CD8 markers.

    • They commit to the T cell lineage and begin rearranging TCR genes.

  • Double-positive Thymocytes (DP):

    • Express both CD4 and CD8 markers and low TCR levels.

    • Await positive selection based on self-MHC binding.

  • Single-positive Thymocytes:

    • CD4+ or CD8+ T cells that have successfully undergone selection and maturation to exit the thymus.

Positive Selection

  • Purpose: Ensures thymocytes have functional receptors that can bind self-MHC molecules, which leads to MHC restriction.

  • Occurs at the double-positive stage; involves interaction with MHC class I or II presented by thymic epithelial cells.

  • Mechanisms include:

    • Death by neglect (failure to bind) or apoptosis for weak binding thymocytes.

Negative Selection

  • Purpose: Eliminates thymocytes that bind too strongly to self-MHC or self-antigens, enabling self-tolerance.

  • Important for preventing autoimmune diseases.

  • Key Players: Dendritic cells, macrophages, and other stromal cells in the thymus mediate this process.

AIRE (Autoimmune Regulator)

  • AIRE expressed in medullary stromal cells helps present a wider array of self-antigens, enhancing negative selection and preventing autoimmunity.

Affinity Hypothesis

  • Theory of T Cell Selection:

    • Cells with no interaction or weak TCR binding (death by neglect).

    • Moderate binding leads to positive selection.

    • High affinity results in negative selection (clonal deletion).

    • Some cells with moderate-high binding can become regulatory T cells (Tregs), which play a role in immune regulation.

Comparison of Mice Models

  • Nude Mouse: Lacks a thymus leading to T cell deficiency due to a lack of functional thymic epithelium.

  • SCID Mouse: Has a defect in lymphocyte development due to inability to rearrange TCR genes; can be repopulated with normal thymic cells.

Cellular Markers and Gene Rearrangement

  • Committed T cell progenitors begin expressing:

    • CD34 (stem cell marker)

    • CD2, CD5, CD44 (adhesion and signaling molecules)

    • CD4, CD8 (co-receptors for T-cell activation).

  • TCR genes have potential for diverse rearrangements (β, γ, δ chain rearrangements).

Conclusion

  • T cell development is a complex process essential for mounting an immune response, ensuring both functionality and self-tolerance through a series of selection processes in the thymus.