T cell activation

Where does the T cell activation take place?

It take places at the secondary lymphoid organ like lymph node or spleen for exemple.

What are the stages 1 of T cell activation?

1. Antigen recognition:

• Naïve T cells circulate through the blood and are directed into secondary lymphoid organs, such as lymph nodes, by adhesion molecules and chemokines. This allows them to search for APCs presenting their specific antigen.

• Inside the lymphoid organ, the T cell encounters antigen-presenting cells (APCs), especially dendritic cells, displaying peptide–MHC complexes.

• The T cell makes an initial contact with the APC through adhesion molecules, particularly LFA-1 on the T cell binding to ICAM-1 on the APC. This allows the T cell to attach and scan peptide–MHC complexes.

• The TCR examines the peptide–MHC complex. If the TCR does not recognize the peptide, the interaction remains weak and the T cell detaches to continue searching.

• If the TCR recognizes its specific peptide–MHC complex, TCR signaling increases LFA-1 affinity, strengthening the LFA-1–ICAM-1 interaction. This produces a stable T cell–APC contact and allows T-cell activation to proceed. If not the T cell will detaches and continue searching for the right complex.

What are the stages 2 of T cell activation?

2. TCR signalling:

• After the TCR has bound to the specific complex of peptide and MHC the co-receptors such as CD4 or CD8 binds to MHC and stabilizes the interaction.

• The TCR α and β chains have short cytoplasmic tails that lack signaling motifs, so they cannot signal on their own. This is where Lck comes in:

Signal 1:

• After TCR recognition, CD4/CD8 brings in the tyrosine Lck kinase to TCR receptors, which phosphorylates the ITAMs (immunoreceptor tyrosine-based activation motif) that has tryosin residues on CD3 and ζ chains.

• Once they are phosphorylated they form binding sites for the next signaling molecules like ZAP-70.

• It is like a docking point for the ZAP-70 which then it gets phosphorylated and activated.

• ZAP-70 phosphorylates LAT and SLP-76.

• LAT + SLP-76 form a signaling platform, recruiting other proteins and activating downstream pathways.

Three major signaling pathways:

1. Ca²⁺ pathway → activates NFAT

2. PKC pathway → activates NF-κB

3. Ras–MAPK pathway → activates AP-1

→ Together, these pathways activate transcription factors, leading to T-cell activation and gene expression, including the production of IL-2. However, Signal 1 alone produces insufficient IL-2 and is not enough for full T-cell activation. Therefore, the T cell requires a second signal (co-stimulation) for full activation.

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ITAM: Is conserved amino-acid sequence in the intracellular tails

ZAP-70: Is tyrosine kinase

Describe the 2 signal of T cell activation?

Signal 2: Confirms the context. It indicates that the APC has encountered infection or danger and that activation is appropriate.

• When the APC are activated they upregulate CD80 and CD86

• CD80/CD86 on the activated APC bind to the CD28 co-stimulatory receptor on the naïve T cell. This provides Signal 2, indicating that the antigen is being presented in an appropriate inflammatory context and that the T cell should proceed with activation.

• After the 2 signal the expression of IL-2 increases which leads to upregulation of CD25 and forming high affinity IL-2 receptor.

• IL-2 binds to the high-affinity IL-2 receptors on the activated T cell itself.

• IL-2 signaling promotes T-cell proliferation and clonal expansion.

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CD80/86 are transmembrane proteins that get expressed om APCs. It is present in Low level on resting B cells and macrophages and, high level on activated dendritic cells. They are induced by IFN-Gamma, CD40/CD40L interactions

They are highly homologous and they have different expression patterns after activation: CD86 is upregulated first, followed by CD80.

How do we control naïve T cells activation?

1. Anergy:

• A T cell needs both Signal 1 and Signal 2 for proper activation.

• Signal 1: TCR recognizes the correct peptide–MHC complex.

• Signal 2: Co-stimulation through CD28–CD80/CD86.

• If the T cell receives Signal 1 but no Signal 2:

  • It produces only a small amount of IL-2.

  • This is not enough to induce significant proliferation.

  • The T cell does not undergo clonal expansion.

  • Instead, it can enter anergy.

• Anergy = the T cell remains alive but becomes functionally unresponsive.

It helps prevent T cells from becoming activated when they recognize an antigen without the appropriate inflammatory/co-stimulatory context

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2. CTLA-4 and PD-1:

• After activation, T cells upregulate CTLA-4.

• CTLA-4 competes with CD28 for CD80/CD86.

• CTLA-4 has a higher affinity for CD80/CD86.

• → Less CD28 co-stimulation → ↓ IL-2 → reduced T-cell activation.

• PD-1 is expressed after T-cell activation.

• PD-1 binds PD-L1 on APCs.

• → Reduces signaling in the activated T cell.

• Particularly important during prolonged immune responses.

Overall: CTLA-4 and PD-1 limit excessive T-cell activation, helping prevent excessive inflammation and tissue damage.

What is the differences between the naive T cell and the Effector or memory T cell?

The difference between them is that the effector and memory cell does not have any co-stimulation signaling because they are already primed.

Why is all this molecular regulation of T cells activation

important?

Understanding how T cells are activated allows us to control

their responses—and to use them as powerful treatments.