Week 4: Applied Immunology Lecture 4b - T Cell Development

Overview

• Focus on T cell maturation in the thymus.
• Processes involved: Beta selection, positive selection, negative selection.
• These processes test the functionality of T Cell Receptors (TCRs) generated through VDJ recombination.
• Builds on previous lectures regarding antigen receptor generation and T cell activation.

T Cell Differentiation

• Hematopoietic stem cells in bone marrow give rise to common lymphoid progenitors (CLPs).
• T cells express TCR that binds to foreign peptides presented by self-MHC molecules.
• Two main selection criteria for functional T cells:
  1. Ability to recognize foreign antigen presented by peptide-MHC.
  2. Non-reactivity to self-antigens to avoid autoimmunity (immune tolerance).

Stages of T Cell Development

1. Origin in Bone Marrow:

   • CLPs undergo commitment towards B-cell, innate lymphoid cells, or T cells.
   • T cell commitment occurs upon egress to the thymus and activation of Notch 1 signaling.

2. Thymic Progenitor Cells:

   • Immature T cells referred to as thymocytes.
   • Development progresses through several stages:
     • Double Negative (DN) Thymocytes:
       • Lack CD4 and CD8 co-receptors.
       • Subjected to beta selection.
     • Double Positive (DP) Thymocytes:
       • Express CD4 and CD8.
       • Undergo positive and negative selection.
     • Single Positive (SP) Thymocytes:
       • Mature naive T cells that express either CD4 or CD8.
       • Exit thymus to secondary lymphoid organs.

Selection Checkpoints

1. Beta Selection

• Tests functionality of TCR beta chain.
• Uses pre-TCR complex (TCR beta + surrogate alpha chain).
• Successful signaling leads to proliferation and transition to DP stage.
• Key points:
  • Allelic exclusion: only one beta chain expressed.
  • Antigen-independent process (does not require peptide-MHC).

2. Positive Selection

• Tests if TCR can recognize self-MHC.
• Ensures MHC restriction.
• Thymocytes that pass this checkpoint further develop into SP thymocytes.
• Antigen-dependent process (requires binding to self-peptide-MHC).

3. Negative Selection

• Removes autoreactive TCR clones that react strongly to self-antigens.
• Ensures central tolerance.
• TCRs with high affinity for self-peptide-MHC are deleted (clonal deletion).
• Also an antigen-dependent process.

Final Outcomes

• Only about 2% of initial thymocytes mature into single positive T cells.
• Importance of checkpoints in filtering out non-functional or autoreactive TCRs.

Anatomical Organization of the Thymus

• Thymus located above the heart, composed of lobes/lobules with cortical and medullary regions.
• Development stages correspond with anatomical regions:
  • Cortex: Immature thymocytes, double negative stages.
  • Medulla: Mature thymocytes, positive and negative selection.

Summary of T Cell Development

• T cell maturation involves progression through beta selection, positive selection, and negative selection.
• Each selection stage ensures functionality and safety of TCRs.
• Successful thymocytes become mature naive T cells ready to respond to antigens in secondary lymphoid organs.

Next Steps

• Upcoming lectures will discuss mature T cell activation and effector functions.