Entry into the cell cycle
Antigen binding to the TCR removes the T lymphocyte from its resting state (G0) and transfers it into the first phase of the cell cycle, G1. However, progression through the cycle is not continuous: the cell pauses at the so-called restriction point, located between the G1a and G1b stages.
To successfully overcome this delay, the T lymphocyte requires cytokines, among which IL-2 holds absolute priority. Cycle progression is strictly controlled by serine/threonine cyclins and cyclin-dependent kinases (Cdks). Cyclins bind to kinases, causing phosphorylation and activation of the latter.
A total of 6 cyclins and 6 kinases (Cdk1–Cdk6) are distinguished. Cyclins are strictly distributed across the phases:
- G1/S cyclins (D and E): prepare the cell for replication of genetic material.
- S cyclin (A): directly initiates the DNA replication process.
- M cyclin (B): is required for the cell to enter mitosis.
Mechanism of progression through division phases
The process of T-lymphocyte cell division represents a cascade of activation of specific protein complexes:
- Entry into the cycle: the primary cyclin E–Cdk2 complex is formed.
- Overcoming the restriction point (G1a/G1b): cyclin D1, D2, D3 complexes are engaged in conjunction with Cdk4 and Cdk6 kinases.
- G1b phase events: the cyclin E–Cdk2 complex phosphorylates the retinoblastoma protein (Rb). This causes the E2F factor to detach from Rb and become activated. E2F is precisely what triggers the expression of genes required for the synthesis of cyclins A and B.
- S phase: DNA replication is initiated by the cyclin A–Cdk2 complex.
- Mitosis: the final stage of division is triggered by the cyclin B–Cdk1 complex.
As soon as a specific cycle phase is completed, the corresponding cyclins undergo degradation. This process is catalyzed by ubiquitin ligase enzymes via ubiquitination.
Role of IL-2 in proliferative expansion
The main source of IL-2 is activated CD4+ T lymphocytes (especially Th1 cells). This cytokine is a fundamental growth factor. When the alpha chain is incorporated into the IL-2 cell receptor, the affinity (binding affinity) of the receptor for the ligand increases dramatically.
The signal from the high-affinity receptor allows the cell to overcome the restriction point (G1a/G1b) and reach mitosis. Importantly, after division is complete, the high-affinity receptor persists on the lymphocyte surface, allowing the cycle to repeat.
During the immune response, an antigen is presented by a dendritic cell, activating both CD4+ and CD8+ T lymphocytes. While CD4+ cells abundantly secrete IL-2, activated CD8+ cells express receptors for it and consume this cytokine for their own proliferation. As a result, T cells undergo 6–8 divisions. The initial clone size (about $2 \times 10^3$ cells) increases hundreds of times over 3–5 days of expansion, exceeding one million cells. This forms a full-fledged pool of effector lymphocytes sufficient for reliable immune defense.
Initiation of T helper differentiation
T cell activation alters its chromatin structure, granting access to cytokine genes. In the early stages following activation, Th0 cells are formed. Their main task is the secretion of IL-2 to ensure proliferation. Other cytokines (IL-3, IL-4, IFN$\gamma$, etc.) are expressed very weakly at the Th0 stage and do not yet play a functional role.
Right during the division process, CD4+ cells begin to differentiate into adaptive subpopulations, the specifics of which depend on the type of pathogen.
| Subpopulation | Typical inducers | Key cytokines (production) | Main function |
|---|---|---|---|
| Th1 | Intracellular pathogens | IFNγ, IL-2, TNFα | Protection against intracellular infections (cell-mediated immunity) |
| Th2 | Parasites, allergens | IL-4, IL-5, IL-13 | Protection against parasites and extracellular pathogens (humoral immunity) |
| Th17 | Extracellular pathogens | IL-17, IL-22, IL-21 | Recruitment of neutrophils for defense against extracellular threats |
To memorize the sequence of cyclin action in the cell cycle (G1/S $\rightarrow$ S $\rightarrow$ M), you can use the abbreviation EDAB: E and D work at the start (G1/S transition), Active replication (S phase), and B at the finale — mitosis (M phase).
What else to study on this topic
- Th1/Th2 dichotomy: how the direction of the immune response is formed
- The role of Tbet, GATA-3, and ROR-C transcription factors in T helper differentiation
- Mechanisms of antigen presentation by dendritic cells
- Pathological role of T helper subpopulations (allergies and autoimmune processes)
- Interaction of CD4+ and CD8+ T lymphocytes during the immune response
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