Regulatory T cells

Discovery and surface phenotype

These lymphocytes were first described by researcher S. Sakaguchi in 1995. A characteristic set of membrane molecules is present on the surface of these cells. The classic human phenotype is described as $CD4^+CD25^{hi}CTLA-4^+GITR^+PD-1^+$.

A crucial distinctive feature is extremely high expression of the CD25 molecule, which represents the alpha chain of the interleukin-2 receptor. It is precisely the high density of CD25 that distinguishes them from conventional activated T helper cells. In addition, the membrane features:

• Suppressive analogues of costimulatory receptors (CTLA-4 and PD-1).
• The GITR protein (Glucocorticoid-induced TNFR-related) from the tumor necrosis factor receptor family.
• A broad repertoire of Toll-like receptors (specifically TLR4).

Their absolute number in peripheral blood is small: approximately 0.02–0.06 × 10⁹ cells per liter, which accounts for about 3–5% of all circulating lymphocytes.

Transcription factor FOXP3

The main intracellular marker and functional "engine" of suppressive activity is the transcription factor FOXP3 (also known as scurfin). The protein has four domains, of which the C-terminal forkhead domain directly provides DNA-binding function.

Experiments convincingly demonstrate the key role of this factor:

1. If the FOXP3 gene is artificially introduced into conventional non-regulatory T cells ($CD4^+CD25^-$), they begin to express CD25, CTLA-4, and acquire the ability to suppress immune responses.
2. In mice with the sf mutation, this gene is damaged, leading to severe pathologies: growth retardation, eczema, severe diarrhea, anemia, and lymphoproliferative syndrome.
3. Any mutation leading to the loss of function of this protein deprives the cells of suppressive activity.

Notably, normally FOXP3 is detected in approximately 10–12% of all blood T lymphocytes, including a small proportion of cells without surface CD25, which can also exhibit regulatory properties.

Development and molecular mechanisms

The bulk of natural regulatory T cells mature in the thymus. The process of their differentiation is closely linked to the sequential induction of the CD25 and FOXP3 genes.

CD25 induction occurs when a thymocyte contacts thymic stromal cells. The Notch3 receptor on the lymphocyte binds to Jagged 1/2 ligands on the stroma. As a result of proteolytic cleavage, the Notch-Maml complex is formed, which travels to the nucleus and triggers CD25 gene transcription.

FOXP3 induction requires the presence of interleukin-2 (IL-2), which is secreted by mature lymphocytes and stromal cells. IL-2 binds to its receptor on the thymocyte, activating Jak1 and Jak3 enzymes. This leads to the phosphorylation and dimerization of the STAT5 factor, which translocates to the nucleus and initiates FOXP3 synthesis.

Thymic dendritic cells, whose activity is stimulated by stromal lymphopoietin TSLP (Thymic stromal lymphopoietin) secreted by Hassall's corpuscles, also actively participate in the induction.

Specific clonal selection

The fate of maturing T lymphocytes depends on the strength of their affinity for self antigens (MHC-peptide complexes). Ordinary lymphocytes with excessively high recognition affinity die (negative selection) to prevent autoimmune aggression.

However, a special mechanism operates for regulatory subpopulations — agonist-dependent selection. They possess high affinity for self-antigens presented by medullary zone cells, but do not die upon contact. FOXP3 expression renders them resistant to apoptosis.

Thus, autoantigens do not destroy these cells, but select them for further function. As a result, they retain the ability to recognize self-tissues, but instead of attacking, they inhibit autoreactive effector clones. The majority of such cells (50–90%) express two different rearranged cellular receptor $\alpha$-chains simultaneously.

Clinical significance: IPEX syndrome

A breakdown in regulatory T lymphocyte development leads to catastrophic consequences. A classic example of human pathology is IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked syndrome).

This severe X-linked disorder arises from a defect in the FOXP3 gene. It is accompanied by the early death of normal CD4+ cells and a massive release of pro-inflammatory cytokines. Clinically, the syndrome manifests as multiple autoimmune endocrine disorders, severe enteropathy, wasting (cachexia), allergies, and hematological abnormalities.

On the other hand, if the FOXP3 gene is overactive (as demonstrated in animal experiments), severe immunodeficiency occurs due to excessive suppression of effector T-cell function.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Stages of adaptive Treg differentiation in the periphery under the influence of TGFβ.
• Interaction of the Notch3 receptor and Jagged 1/2 ligands in the thymus.
• The role of MHC-II and AIRE genes in the positive selection of regulatory cells.
• Similarities and differences between Tregs and the invariant NKT cell population.

Other topics in the "Adaptive Immunity" section

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