Why is selection needed?
The initial repertoire of T-cell receptors (TCR) is formed randomly, so many of them are unable to recognize the MHC (major histocompatibility complex) or, conversely, react too aggressively against the body's own antigens. To prevent inefficiency or the development of autoimmune diseases, thymocytes undergo rigorous selection in the thymus, consisting of two main stages.
Positive selection
At this stage, cells whose receptors are fundamentally capable of recognizing MHC-peptide complexes are selected.
- Where it occurs: in the thymic cortex.
- Who participates: double-positive thymocytes (CD4+CD8+) and cortical thymic epithelial cells.
- Mechanism: thymocytes interact with MHC class I and II molecules on epithelial cells.
- Outcome: if the receptor has affinity for MHC, the thymocyte receives a survival signal (upregulation of the anti-apoptotic factor Bcl-2). If there is no affinity, the cell dies by apoptosis. About 90% of thymocytes are eliminated at this stage.
Negative selection
The goal of this stage is to destroy cell clones that react too strongly to the body's own antigens (autoreactive clones).
- Where it occurs: at the corticomedullary junction and the medulla of the thymus.
- Who participates: thymocytes that have passed positive selection, medullary dendritic cells, and epithelial cells.
- Mechanism: the degree of TCR affinity for the "MHC–peptide" complex of self-tissues is evaluated.
- Outcome: cells with high affinity undergo apoptosis (elimination marker — nuclear factor Nur77). Only cells with moderate (intermediate) affinity survive.
An important role here is played by the AIRE gene, which prompts thymic cells to synthesize proteins of other organs (ectopic expression) to "test" thymocytes for autoaggression against the tissues of the entire organism.
Differentiation into CD4+ and CD8+ cells
In parallel with selection, double-positive thymocytes (CD4+CD8+) must choose their specialization. This choice depends on the strength of the signal from the TCR and which MHC class the receptor interacts with:
- CD4+ (T helper cells): formed upon a strong signal from the TCR recognizing MHC-II. The main transcription factors are Th-POK and GATA-3.
- CD8+ (cytotoxic T lymphocytes): formed upon a weak signal from the TCR recognizing MHC-I. Key factors are Tox and Runx3.
If the receptor specificity for the MHC class does not match the remaining coreceptor (e.g., TCR recognizes MHC-I, but the cell retains CD4), such a thymocyte dies.
Briefly: answers to topical questions
What stages do thymocytes go through before turning into double-positive (CD4+CD8+) cells?
Before turning into double-positive cells, thymocytes pass through double-negative stages, including pro-T and pre-T cells.
- DN2 stage — characterized by the $CD44^+ CD25^+$ phenotype.
- DN3 stage — stage 3 double-negative thymocytes with the $CD44^- CD25^+$ phenotype.
It is at these stages that T-cell receptor gene rearrangement and the choice of differentiation pathway occur.
How is the primary diversity of T-cell receptors (TCR) formed?
The primary diversity of T-cell receptors is formed by random rearrangement (recombination) of receptor genes in maturing lymphocytes. The process is triggered by the expression of genes of the V(D)J recombination complex and includes the following stages:
- D-J recombination — approximation and joining of D and J segments.
- V-DJ recombination — full-scale rearrangement with the attachment of the V segment to the DJ tandem.
The rearrangement occurs in the 3'-terminal part of the V gene, forming the third hypervariable region (CDR3), the variability of which significantly exceeds other regions. This primary repertoire of receptors is not tied to the actual needs of the immune system.
How are natural regulatory T cells (nTreg) generated in the thymus?
Natural regulatory T cells develop in the thymus from CD4+CD25- thymocytes via sequential expression of CD25 and FOXP3 genes. The process includes:
- CD25 induction — interaction of the Notch-3 receptor on thymocytes with the Jagged 1/2 ligand on stromal cells.
- FOXP3 induction — binding of IL-2 to its receptor with the participation of the STAT5 factor.
- Agonist-dependent selection — survival of cells upon contact with dendritic and epithelial cells presenting autologous peptides with high affinity.
As a result, cells acquire suppressive properties while avoiding negative selection.
Which cells phagocytose thymocytes that die as a result of selection?
Thymocytes that die during development and selection are cleared by thymic macrophages. Thymic macrophages are tissue-specific resident macrophages.
P-N-D: Positive (fitness check) -> Negative (safety check) -> Differentiation (career choice).
Class and exam questions
What is the essence of the TCR signaling paradox?
A signal through the same receptor (TCR) during positive selection rescues the cell from death, whereas during negative selection, it triggers apoptosis. This is due to the activation of different intracellular cascades depending on the strength of the receptor's affinity for the ligand.
What role does the AIRE gene play?
The AIRE gene ensures the expression of organ-specific antigens (proteins of other organs) in the thymus. This is necessary to remove T cells capable of attacking the body's own tissues during negative selection. Mutations in the gene lead to severe autoimmune diseases.
What happens to a thymocyte if it does not recognize MHC at all?
Such a thymocyte dies by apoptosis "by default" already at the positive selection stage, as it fails to receive a survival signal from the microenvironment.
What else to study on this topic
- Intracellular signaling during selection (MAP cascade, c-Fos, c-Jun factors)
- Molecular mechanisms of T-cell emigration from the thymus (S1P-1 receptor)
- Additional peripheral mechanisms of defense against autoaggression
- T-lymphocyte subpopulations (classical and non-classical)
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