Mechanisms of tolerance induction
For full activation, a T lymphocyte requires not only recognizing the antigen via its receptor, but also receiving an additional confirmatory signal. The main mechanism of anergy development, which operates both in the thymus (central organ) and in the periphery, is the absence of the costimulatory signal.
This occurs in two main variants:
- Defect on the antigen-presenting cell (APC) side: absence of costimulatory molecules (primarily B7) on the surface of cortical thymic epithelial cells (cTECs) in the thymus or on somatic cells in peripheral tissues.
- Defect on the lymphocyte side: absence of receptor molecules (CD28) directly on the membrane of maturing thymocytes.
If a T cell "sees" the antigen but does not receive a signal through the CD28-B7 axis, it fails to activate and instead transitions into a dormant, anergic state.
Molecular alterations within the anergic cell
The lack of costimulation results in a critical attenuation of intracellular signal transduction from the T-cell receptor. This triggers a cascade of molecular failures:
- Impairment of transcription factors. Of the three main factors that should be activated upon antigen presentation, the synthesis of AP-1 (which is a dimer of c-Fos and c-Jun proteins) suffers the most.
- Drop in gene expression. Defective signal transduction through the TCR/CD28 complex leads to a sharp decrease in the expression of the interleukin-2 (IL-2) gene. This cytokine is vital for full T-cell proliferation and activation.
- Activation of inhibitors. During the development of anergy, an important role is played by the Cbl-b factor, which acts as an active intracellular inhibitor of activation.
The logical outcome of such profound molecular changes is apoptosis—accelerated programmed death of the unresponsive cell.
Experimental evidence of peripheral anergy
The existence of anergy as a mechanism of peripheral tolerance was brilliantly proven in experiments on transgenic mice.
Researchers took mice with a baseline H-2ª genotype and introduced two additional genes:
- H-2ᵇ genes, which were artificially forced to be expressed only in pancreatic cells.
- Genes for the T-cell receptor (TCR) specific precisely to H-2ᵇ molecules (expressed in T lymphocytes).
What did the experiment show? In the thymus, maturing T cells readily recognized H-2ᵇ and generated fully functional specific killer T cells. That is, physical destruction (elimination) of this clone did not occur in the central organ of the immune system. However, when these same killer T cells migrated to the periphery (where the H-2ᵇ target awaited them in the pancreas), they did not react to it at all.
The researchers discovered that these unresponsive T lymphocytes are temporarily present in the peripheral circulation. This served as direct proof that peripheral tolerance is maintained through T-clone anergy rather than solely via its complete physical elimination in the thymus.
Note: Unlike T cells, inducing a similar state of anergy in B lymphocytes is a much more complex and difficult process to study.
Briefly: answers to topical questions
What are the main differences between central and peripheral tolerance?
The main differences between central and peripheral tolerance lie in their implementation mechanisms and the sites where the processes occur.
| Characteristic | Central tolerance | Peripheral tolerance |
|---|---|---|
| Site of occurrence | Thymus (for T cells) and bone marrow (for B cells) | Peripheral compartment of the immune system |
| Primary mechanism | Elimination (apoptosis) of autoreactive clones during negative selection | Anergy (functional inactivation), receptor editing, and control by regulatory T cells |
| Efficacy | Serves as the most efficient mechanism, though it does not reach 100% | Acts as an additional barrier to prevent autoaggressiveness |
What are the differences in anergy induction between T and B lymphocytes?
The differences in anergy induction between T and B lymphocytes lie in the induction conditions, required antigen dose, and stability of the state.
| Characteristic | T lymphocytes | B lymphocytes |
|---|---|---|
| Main induction factor | Lack of costimulation—CD28 molecules on the T cell or B7 on the antigen-presenting cell—upon antigen recognition | Reaction of an immature B cell with a soluble autoantigen |
| Antigen dose requirements | T-helper tolerization is usually sufficient to prevent the development of the entire immune response | Significantly higher antigen doses are required |
| Stability and outcome | Accelerated cell death via apoptosis is the usual outcome | The state is less stable; an anergic B cell with high IgD expression is formed |
Which signaling pathways are blocked in the absence of CD28-B7 costimulation?
In the absence of CD28–B7 costimulation, signaling pathways dependent on CD28 costimulation are attenuated, impairing the full engagement of protein kinase Cθ.
The following signaling events are disrupted or attenuated:
- PI3K activation — the enzyme is physically associated with CD28; PI3K participates in the formation of phosphatidylinositol-4,5-bisphosphate.
- Vav activation — a nodal factor required for cytoskeleton engagement, recruitment, and activation of PKCθ.
- PKCθ recruitment — the transport of this isoform to the immunological synapse depends on PI3K and Vav.
- Engagement of the Rac/JNK branch of the MAP cascade — this branch is maximally dependent on PKCθ and costimulation.
- Formation of AP-1 and NF-κB transcription factors — these processes are critically linked to PKCθ; anergy most severely impairs AP-1 formation, accompanied by a decrease in IL-2 gene expression.
Class and exam questions
What is the main cause of T-lymphocyte anergy development?
Anergy develops due to the absence of a costimulatory signal (interaction between B7 molecules on the APC and CD28 on the T cell) at the moment the lymphocyte receptor recognizes the antigen.
Synthesis of which cytokine is impaired the most during anergy?
The expression of the interleukin-2 (IL-2) gene, which is critical for T-lymphocyte activation and proliferation, drops the most.
Which transcription factor is blocked during anergy?
The formation of the AP-1 factor, consisting of a dimer of c-Fos and c-Jun proteins, is impaired to the greatest extent.
What is the ultimate fate of the anergic T cell?
The usual outcome of profound anergy is accelerated lymphocyte death via programmed cell death — apoptosis.
What else to study on this topic
- Interaction of B7 and CD28 molecules: normal costimulation mechanisms
- The role of transcription factor AP-1 (c-Fos/c-Jun) in the immune response
- Functions of interleukin-2 (IL-2) in lymphocyte activation
- Cbl-b protein as an inhibitor of T-cell activation
- Differences in anergy mechanisms between T and B lymphocytes
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