Skip to content

Topic 3 T Cell

1. T Cell Development (The "Education" Phase)

  • Origin: Starts in the Red Bone Marrow as a T cell precursor.

  • Migration: Travels to the Thymus (primary lymphoid organ).

    • Mechanism: Thymus releases chemotactic agents (e.g., thymosin) to attract T cell precursors.

Step 1: Receptor Formation (Gene Shuffling)

  • Trigger: Chemotactic agents bind to the naive T cell's receptor.

  • Action: Activates RAG1 and RAG2 (Recombination-Activating Genes).

  • Result: These recombinases shuffle DNA segments to create a unique TCR (T Cell Receptor).

    • Goal: Create a receptor specific for one unique antigen (Note: TCRs bind Antigen-MHC complexes, not antibodies directly).

Step 2: Lineage Commitment (The "Double Positive" Stage)

  • T cells initially express both CD4 and CD8 (Double Positive).

  • CD8: Binds to MHC Class I.

  • CD4: Binds to MHC Class II.

Step 3: The Exams (Selection Process)

  1. Positive Selection (The "Competence" Test):

    • Question: Can this TCR recognize my own MHC molecules?

    • Process: Thymic epithelial cells present MHC.

    • Pass: TCR binds MHC with moderate affinity (Survival signal received).

    • Fail: No binding $\rightarrow$ Death by Neglect (Apoptosis).

  2. Negative Selection (The "Loyalty" Test):

    • Question: Does this TCR attack "self" tissues?

    • Process: Thymic cells present "self-peptides" on MHC.

    • Fail: High-affinity binding to self $\rightarrow$ Clonal Deletion (Apoptosis triggered by FAS ligand released by thymic cells).

    • Pass: Low/No binding to self $\rightarrow$ Survives.

Step 4: Final Maturation & Choice

  • The Choice:

    • Upregulate CD4, Downregulate CD8 $\rightarrow$ T Helper Cell (Th) $\rightarrow$ Secondary Lymphoid Organs.

    • Upregulate CD8, Downregulate CD4 $\rightarrow$ T Cytotoxic Cell (Tc) $\rightarrow$ Secondary Lymphoid Organs.

  • The Exception (Treg):

    • Some self-reactive CD4+ cells are not killed but diverted to become Natural Tregs.

    • Location: Occurs mainly in Hassall’s Corpuscles in the thymus.

    • Mechanism: Upregulate CD25 and FoxP3 (dependent on IL-2).

2. Classification Cheat Sheet

A. The "Rule of 8"

  • CD4 x MHC II = 8 (Helpers talk to Generals/APCs).

  • CD8 x MHC I = 8 (Killers check Civilians/Nucleated cells).

B. CD4+ Helper T Lineages

Input Cytokines $\rightarrow$ Master Transcription Factor $\rightarrow$ Output Cytokines

Lineage Input (Induction) Master Switch Output (Effector) Main Function
Th1 IL-12, IFN-$\gamma$ T-bet IFN-$\gamma$, TNF Intracellular Defense: Viruses, bacteria inside macrophages.
Th2 IL-4 GATA3 IL-4, IL-5, IL-13 Extracellular Defense: Parasites (Worms), Allergy.
Th17 Mouse: TGF-$\beta$ + IL-6



Human: TGF-$\beta$ + IL-1$\beta$ + IL-6		 ROR$\gamma$t IL-17, IL-22 Mucosal Defense: Fungi, Extracellular bacteria. Autoimmunity driver.
Treg TGF-$\beta$, IL-2 FoxP3 TGF-$\beta$, IL-10 Suppression: Immune tolerance, preventing autoimmunity.
Tfh IL-6, IL-21 Bcl6 IL-21 B Cell Help: Antibody production.

C. Unconventional T Cells

Cell Type Recognition Target Key Feature
NKT Cells Lipids on CD1d Bridge Innate/Adaptive. Rapid cytokine release.
$\gamma\delta$ T Cells Stress Signals & Phosphoantigens No MHC required. Barrier defense (Skin/Gut).

3. Cell-Mediated Immunity (The Killers)

This is the detailed section you requested on how cells kill.

A. Cytotoxic T Lymphocytes (CTLs)

  • Identity: CD8+, Adaptive Immunity.

  • Target: Virus-infected cells, Tumor cells, Intracellular bacteria.

  • Recognition: TCR binds to specific Antigen + MHC Class I.

  • Mechanism of Killing:

    1. Perforin/Granzyme Pathway (Main):

      • CTL releases granules.

      • Perforin: Punches holes (pores) in the target cell membrane.

      • Granzymes: Enter through holes and activate Caspases inside the target.

      • Result: Apoptosis (clean cell suicide).

    2. Fas Ligand (FasL) Pathway:

      • CTL expresses FasL on its surface.

      • Binds to Fas receptor (CD95) on the target cell.

      • Result: Triggers the "Death Domain" signal cascade $\rightarrow$ Apoptosis.

B. Natural Killer (NK) Cells

  • Identity: Innate Lymphoid Cell (No TCR), Innate Immunity.

  • Target: Cells trying to "hide" from CTLs by removing MHC I, or stressed cells.

  • Recognition (The "Missing Self" Hypothesis):

    • Inhibitory Receptor: Binds to Normal MHC Class I. If detected $\rightarrow$ "Don't Kill."

    • Activating Receptor: Binds to Stress Ligands (e.g., MICA/MICB) on infected cells.

    • Trigger: Low MHC I + High Stress Signal = KILL.

  • Mechanism: Uses Perforin and Granzymes (same as CTL).

  • ADCC (Antibody-Dependent Cell-mediated Cytotoxicity):

    • NK cells have CD16 (Fc Receptor).

    • If a target is coated in antibodies (IgG), CD16 binds the antibody tail.

    • Result: NK cell degranulates and kills the target.

Tregs

  • Immune tolerance, preventing autoimmunity.
  • access a unique transcription factor called FOXP3
  • Further subtypes
    • natural Tregs (nTregs): in peripheral immune tolerance
    • induced Tregs (iTregs): naive T cells; control inflammation
  • Produce anti-inflammatory cytokines: IL-10 and TGF-$\beta$
    • inhibit other immune cells; cause the cytolysis of activated T cells
  • Metabolic regulation
    • reduce the level of glucose and amino acids that is necessary for other immune cells
  • Moderate DC cells
    • prevent DC cells --> prevent other immune cells
  • Regulating cancer and infections
    • suppressing the immune cells --> targeting cancer cells
    • prevent immune mediated damage to host tissue and promote immune tolerance