Start: From receptor to initial kinases
The initial inducer of activation is an antigenic stimulus. Since the membrane receptor itself (TCR) cannot migrate to the nucleus, the cell uses a cascade signal transmission principle. The interaction of the MHC-antigen complex with the TCR and coreceptor (CD4) induces conformational changes in the complex.
This engages proximal membrane-bound tyrosine kinases of the Src family — the enzymes Lck (associated with CD4) and Fyn (associated with CD3). Interestingly, in a resting cell, the Lck enzyme is locked in a folded conformation (due to phosphorylation of the inhibitory tyrosine residue Y505). For the kinase to be activated, the CD45 phosphatase cleaves off the phosphate group, the molecule unfolds, and its active site becomes accessible. The main task of these initial kinases is to phosphorylate specific ITAM motifs on the intracellular segments of the receptor complex polypeptide chains.
Zeta chain and pathway divergence (ZAP-70 and LAT)
A special role in signal transduction is played by the ζ-chain (zeta chain) of the TCR receptor, which carries as many as three ITAM sequences. The level of their phosphorylation directly determines the fate of the T lymphocyte:
- 0 groups: apoptosis;
- 1 group: binding of a low-affinity ligand, survival of a resting cell;
- All groups: binding of a high-affinity ligand during prolonged contact, triggering of activation.
The tyrosine kinase ZAP-70, belonging to the Syk family, binds to the phosphorylated regions. Activated by the Lck kinase, it transmits the signal to the membrane adaptor protein LAT (Linker for activation of T-cells). Phosphorylated LAT acts as a docking station, recruiting many other molecules (SLP-76, Grb2, Vav, PLCγ1), which branches the signal into independent pathways.
Five signaling pathways to the nucleus
Five main intracellular cascades originate from the LAT protein, with the nucleus as their ultimate destination:
- Calcium-dependent pathway: The enzyme PLCγ1 cleaves the membrane lipid PIP2 into two messengers — DAG (remains in the membrane) and IP3 (goes into the cytoplasm). IP3 opens calcium stores in the endoplasmic reticulum, ultimately triggering an avalanche-like influx of extracellular $Ca^{2+}$. Calcium activates the phosphatase calcineurin, which dephosphorylates the NF-AT transcription factor, allowing it to enter the nucleus.
- NF-κB pathway: Regulated via an enzyme cascade (including IKK) and leads to the degradation of the IκB inhibitor, releasing the active NF-κB factor.
- MAP kinase branches (ERK, JNK, p38): A complex network of reactions involving small G proteins (Ras, Rac), Raf and MEK kinases. Results in the synthesis and activation of c-Jun and c-Fos subunits, which assemble into the AP-1 factor.
Role of costimulation and PKCθ
For a full immune response, a signal solely from the TCR receptor is insufficient; costimulation via the CD28 molecule is required. The duality of the signal is clearly demonstrated by the specific PKCθ (theta) kinase.
The transport of PKCθ to the immune synapse depends on the co-stimulatory pathway (via PI3K and CD28), whereas enzymatic activation depends on the receptor pathway (via the Lck kinase). Only at the intersection of these two signals can PKCθ perform its functions: prevent cell apoptosis and activate the NF-κB and AP-1 transcription factors. The ultimate outcome of all pathways is the binding of transcription factors to the promoters of target genes (e.g., CD25), which transitions the T cell into an active state.
Briefly: answers to topical questions
What target genes are turned on by transcription factors following T lymphocyte activation?
Following T lymphocyte activation, transcription factors trigger the expression of target genes necessary for proliferation and differentiation. These primary genes include:
- Interleukin-2 gene (IL2) — its transcription is triggered by NF-κB, AP-1, and mature NF-AT factors.
- Interleukin-2 receptor gene (IL2R or CD25) — expressed to support IL-2-dependent processes and proliferation.
The binding of transcription factors to the promoter regions of these genes on DNA initiates their transcription.
What proteins and polypeptide chains make up the complete TCR receptor complex?
The complete T-lymphocyte receptor complex includes:
- Antigen-recognizing TCR dimer — an αβ or γδ dimer composed of variable and constant domains.
- CD3 complex — γ, δ, and ε chains forming εγ and δε heterodimers, as well as receptor-associated ζ chains.
- ζ dimer (CD247) — a ζζ homodimer; the cytoplasmic portion of the ζ chains contains three ITAM motifs each.
- CD4 or CD8 coreceptor.
- Proximal tyrosine kinases Lck and Fyn associated with the receptor complex: Lck is associated with CD4, and Fyn with CD3.
Which molecules provide the costimulatory signal during T lymphocyte activation?
The costimulatory signal during T-lymphocyte activation is provided by the interaction of paired molecules on the surface of the T cell and the antigen-presenting cell (APC). Key costimulatory molecules include:
- CD28 receptor — interacts with CD80 (B7-1) and CD86 (B7-2) ligands on the APC, providing the primary activating signal and IL-2 secretion.
- ICOS receptor — binds to the ICOSL ligand, stimulating cytokine secretion.
- OX40 receptor — interacts with the OX40L ligand on the APC.
- CD40L molecule (CD154) — binds to the CD40 receptor constitutively expressed on APCs.
What cytokines are secreted by an activated Th1 lymphocyte?
Products of Th1 cells include:
- Interferon-γ (IFNγ).
- Tumor necrosis factor α (TNFα) — contributes significantly to Th1 activity, especially in combination with IFNγ.
- Lymphotoxin α — is a product of Th1 cells.
- Interleukin-10 (IL-10) — in humans, it can be produced by Th1 cells and is classified as a suppressive cytokine.
For quick memorization of the outcomes of ζ-chain ITAM motif phosphorylation: 0 — death (apoptosis), 1 — sleep (survival without activation), 3 — start (full activation of the immune response).
Class and exam questions
What is the role of the CD45 molecule at the early stage of activation?
CD45 is a phosphatase that removes the inhibitory phosphate group from the Lck kinase, unfolding its molecule and preparing the enzyme to phosphorylate the ITAM motifs.
How does the immunosuppressant cyclosporine A work?
It binds to the protein cyclophilin and in this form blocks the calcineurin enzyme. Consequently, the NF-AT transcription factor cannot enter the nucleus, interrupting the T-cell activation process.
What happens if the TCR $\zeta$-chain is not phosphorylated at all?
The T lymphocyte will undergo apoptosis. Basic survival of a resting cell requires homeostatic phosphorylation of at least one ITAM motif.
What else to study on this topic
- Structure and functions of SH1, SH2, and SH3 domains of Src-family tyrosine kinases
- Differences between activating (ITAM) and inhibitory (ITIM) motifs of immunoreceptors
- Mechanism of phosphoinositide metabolism: generation and functions of IP3 and DAG
- Assembly of the signaling complex (SLP-76, Vav, Nck) and its connection to cytoskeleton remodeling
- Detailed diagrams of MAP kinase cascade branches (role of Grb2 and Sos proteins)
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