T-Cell Development

Overview – T-Cell Development

T-cell development is a tightly regulated, multi-stage process by which hematopoietic stem cells differentiate into immunocompetent T lymphocytes. This occurs predominantly in the thymus and continues in peripheral lymphoid organs. The goal of T-cell development is to generate a diverse, self-tolerant, and antigen-responsive pool of T-cells — essential for adaptive cellular immunity. T-cell development ensures both central tolerance (via positive and negative selection) and the generation of CD4 and CD8 T-cells with distinct roles in immune defence.

Development in the Thymus

Step 1 – Entry of Double-Negative Thymocytes

  • Immature T-cell precursors (double-negative thymocytes; no CD4 or CD8 expression) enter the thymus via high endothelial venules (HEVs) at the cortico-medullary junction
  • Migrate to the subcapsular region, where TCR gene rearrangement begins
T-cell development: Step 1 – Double Negative Thymocytes Enter Thymus
Step 1 – Double Negative Thymocytes Enter Thymus
Step 1 – Double Negative Thymocytes Enter Thymus
Source: Unattributable

Step 2 – TCR Gene Rearrangement

  • β (or δ) chain rearrangement: V, D, J segments recombine
  • α (or γ) chain rearrangement: V and J segments recombine
  • Two TCR lineages:
    • αβ T-cells (majority): become CD4 or CD8 cells
    • γδ T-cells (minority): innate-like, non-MHC restricted, epithelial-resident
  • Key enzymes: RAG-1, RAG-2 recombinases and ligases
  • Result: T-cells with diverse TCRs, each specific to a unique antigen-MHC complex
T-cell development: Step 2 – TCR-Gene Rearrangement
Source: Unattributable

Step 3 – TCR Expression

  • TCR proteins are expressed on the cell surface of developing thymocytes

Step 4 – Differentiation into Double-Positive (DP) Thymocytes

  • Thymocytes express both CD4 and CD8 → now termed double-positive
  • Migrate into the cortex of the thymus

Step 5 – Positive Selection (Cortex)

  • Thymic epithelial cells present self-peptides on MHC-I and MHC-II
  • Thymocytes that successfully bind:
    • MHC-I → retain CD8 expression → become CD8+ T-cells
    • MHC-II → retain CD4 expression → become CD4+ T-cells
  • Cells that fail to bind either MHC class receive no survival signal → apoptosis

Step 6 – Negative Selection (Medulla)

  • CD4 and CD8 single-positive thymocytes move to thymic medulla
  • Encounter medullary APCs presenting self-antigen
  • Thymocytes that bind too strongly are deleted → prevents autoimmunity
  • Ensures central tolerance

Step 7 – Exit of Mature Naive T-Cells

  • Surviving CD4 and CD8 naive T-cells exit the thymus
  • Enter peripheral circulation and home to secondary lymphoid organs
T-cell development: Tolerance
CNX OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons

Activation in Peripheral Lymphoid Organs

Step 8 – Antigen Recognition

  • APCs present peptide antigens on MHC-I or MHC-II
    • CD4 T-cells → recognise MHC-II:peptide
    • CD8 T-cells → recognise MHC-I:peptide
  • TCRs do not bind whole antigen — peptide must be MHC-bound
  • Exception: superantigens bypass this restriction (see MHC section)

Step 9 – T-Cell Activation

Three signals are required for full T-cell activation:

  1. Activation Signal – TCR binds to MHC:peptide complex
    • CD4 binds to MHC-II
    • CD8 binds to MHC-I
  2. Survival Signal – Co-stimulation:
    • CD28 binds to CD80/CD86 on APC
    • CD40 binds to CD40L (especially in CD4+ T-cells)
    • 4-1BB binds to its ligand (CD8-specific)
    • Triggers IL-2 synthesis → drives proliferation
  3. Differentiation Signal – Cytokines from APCs or innate immune cells:
    • IL-12, IFN-γ → Th1
    • IL-4 → Th2
    • IL-6, TGF-β → Th17
    • IL-10, TGF-β → T-reg
    • IL-2 → promotes CD8 differentiation
T-cell development: Step 9 – T-Cell Activation
CNX OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons : Clonal Selection and Expansion of T Lymphocytes Stem cells differentiate into T cells with specific receptors, called clones. The clones with receptors specific for antigens on the pathogen are selected for and expanded.
Signal, APC Surface Molecules & Binding Partners

Effector Functions

CD4 Helper T-Cells

  • Recognise MHC-II:peptide (extracellular pathogens)
  • Th1: Activate macrophages, assist CD8 and B-cells (via IFNγ, IL-2, CD40L)
  • Th2: Support B-cell antibody class-switching (via IL-4, IL-5, TGF-β)
  • Th17: Recruit neutrophils (via IL-17)
  • T-reg: Suppress immune responses (via IL-10, TGF-β)

CD8 Cytotoxic T-Cells

  • Recognise MHC-I:peptide (intracellular pathogens, cancer)
  • Kill target cells via cytotoxic granules:
    • Perforin, Granzymes, Granulysin
    • Activate caspases or death receptors (e.g. Fas) → Apoptosis
  • Also secrete:
    • IFNγ (inhibits viral replication)
    • TNFα (pro-inflammatory)
T-cell development: Step 10 – Effector Functions
CNX OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons : Pathogen Presentation (a) CD4 is associated with helper and regulatory T cells. An extracellular pathogen is processed and presented in the binding cleft of a class II MHC molecule, and this interaction is strengthened by the CD4 molecule. (b) CD8 is associated with cytotoxic T cells. An intracellular pathogen is presented by a class I MHC molecule, and CD8 interacts with it.

Memory T-Cells

  • Long-lived, persist at higher levels than naive cells
  • Rapidly respond to repeat antigen exposure
  • Can quickly differentiate into effector cells
T-cell development: Step 9 – T-Cell Activation
CNX OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons

Summary – T-Cell Development

T-cell development begins in the thymus with TCR gene rearrangement and selection, followed by peripheral activation and functional differentiation into helper, cytotoxic, or regulatory T-cells. Each stage ensures self-tolerance and immunocompetence. Mature T-cells are essential for cell-mediated immunity, playing roles in pathogen clearance, immune regulation, and immune memory. For more, see our Immune & Rheumatology Overview page.

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