Lesson 6.2

Learning Objectives

• After completing this session, the learner should be able to:

  • Describe the stages of T cell development from hematopoietic stem cells in the bone marrow to mature T cells in the thymus.

  • Recognize positive and negative selection during T cell development.

  • Describe the process of T cell activation.

  • Understand T cell-mediated immune responses.

T Cell Development

• Overview

  1. T cells develop from stem cells in the bone marrow but complete their maturation in the thymus.

  2. The thymus comprises lobules that contain:

  • An outer cortex

  • An inner medulla

  1. The stages of development are indicated by the presence/absence of cell surface markers including:

  • TCR (T Cell Receptor)

  • CD3

  • CD4

  • CD8

Structure of the Thymus

• Anatomy

  • The thymus is situated near the heart and lungs, and includes structures such as:

  • Capsule: The protective outer covering of the thymus.

  • Trabeculae: Extensions of the capsule that create lobules within the thymus.

  • Cortex: Contains cortical epithelial cells providing a supportive environment for thymocyte development.

  • Medulla: Contains medullary epithelial cells and structures such as Hassall's corpuscles.

  • The thymus hosts various immune cells:

  • Thymocytes (originating from bone marrow)

  • Dendritic cells (originating from bone marrow)

  • Macrophages (originating from bone marrow)

T Cell Development Stages

• T-cell precursors initially originate in the bone marrow but develop and mature in the thymus:

  1. Proliferation: T-cell precursors proliferate extensively in the thymus, although the majority of them die during this process.

  2. Lineage Commitment: Thymocytes commit to distinct lineages:

  • α:β T cells evolve into two functional subsets:

    • CD4 T cells.

    • CD8 T cells.

  1. This process generates T cells that recognize self-MHC through positive selection and become self-tolerant via negative selection.

Positive Selection

• Definition: The process by which T cells that can adequately recognize MHC molecules are allowed to survive.

• Location: Occurs in the thymic cortex.

• Mechanism:

  1. Mediated by thymic cortical epithelial cells expressing both MHC Class I and II proteins.

  2. If a thymocyte fails to recognize an MHC molecule within 3 to 4 days of initial α:β expression, it undergoes apoptosis (cell death).

  3. Cortical epithelial cells provide a survival signal that promotes the survival of thymocytes recognizing MHC.

Co-receptor Selection

• Definition: A selection process that influences which co-receptor (CD4 or CD8) remains active on the T cell.

• Mechanism:

  1. Upon recognition of an MHC molecule by one co-receptor, the other co-receptor gene undergoes downregulation.

  2. Thymocytes that express CD4LOW CD8HIGH survive by recognizing MHC Class I molecules, while those that express CD4HIGH CD8LOW survive by recognizing MHC Class II molecules.

  3. Cortical epithelial cells deliver maturation signals upon successful co-receptor recognition.

Negative Selection

• Definition: The elimination of thymocytes that exhibit strong affinity for self-peptide:MHC complexes.

• Location: Occurs in both the thymic cortex and medulla.

• Mechanism:

  1. This process is mediated by cortical epithelial cells, macrophages, and dendritic cells.

  2. If a thymocyte recognizes a self peptide:MHC complex too strongly, it undergoes apoptosis.

  3. Different binding affinities to the MHC-peptide complex mediate survival (positive selection) or death (negative selection).

  4. Self-peptides derive from both thymic and ubiquitous proteins via the bloodstream.

  5. Thymocytes that successfully survive positive selection, co-receptor selection, and negative selection are deemed single positive, self-tolerant naïve T cells.

T Cell Activation

• Overview: The process of T cell activation that occurs in response to antigen recognition.

• Stages:

  1. Recognition of the MHC:peptide complex by T cells (via Dendritic Cells or DCs), which indicates antigen recognition.

  2. Delivery of a co-stimulatory signal (e.g., B7:CD28) which is critical for T cell activation.

  3. Entry into the cell cycle (specifically the G1 phase), leading to T cell proliferation (clonal expansion).

  4. This proliferation is mediated by IL-2, which also facilitates the differentiation of T cells into effector cells.

  5. Cytokines secreted by Antigen Presenting Cells (APCs) dictate the type of effector T cell each T cell differentiates into.

Types of Signals Delivered to Naive T Cells by APCs

1. Activation Signal: Delivery of a specific signal indicating antigen interaction.

2. Survival Signal: Ensures persistence and survival of activated T cells.

3. Differentiation Signal: Guides T cells to develop into specific effector types based on the environment and signals received (e.g., cytokines like IL-6, IL-12, TGF-β, IL-4).

T Cell Mediated Immunity

• Circulation: Naive T cells continuously circulate in the blood and lymphatic system:

  • CD8+ T cells and CD4+ T cells move between blood and lymphatics (involving T cell and antigen co-stimulation).

  • Types include:

  • CD8+ Cytotoxic T Cells (Tc Cells)

  • CD4+ Helper T Cells (TH1, TH2, TFH Cells)

• Mechanism of Action:

  1. Mediated by Cell Adhesion Molecules (CAMs).

  2. T cells monitor MHC:peptide complexes presented by APCs specifically in lymphoid tissues.

Summary of Key Concepts

1. T cell development is a complex process originating from hematopoietic stem cells and culminating in mature T cells within the thymus.

2. Positive selection ensures the survival of T cells that effectively recognize self-MHC molecules, while negative selection is crucial to eliminate those with high affinity for self-antigens.

3. The activation of T cells is initiated by antigen recognition alongside co-stimulation, leading to their differentiation into various effector T cell subsets.

4. T cells fulfill essential roles in immune defense mechanisms, playing pivotal roles against intracellular pathogens, cancer cells, and infected host cells.