Activation and cross-presentation
Primary activation of naive CD8+ T cells cannot occur upon contact with an ordinary infected cell — this requires a professional antigen-presenting cell (APC), most commonly a dendritic cell. If the virus does not infect the APC directly, a delicate mechanism of cross-presentation (cross-presentation) comes into play.
Extracellular viral antigens are captured via endocytosis, but instead of the classical lysosomal pathway, they are directed into the cytosol and incorporated into MHC-I molecules (rather than MHC-II). For successful induction of the response, the T lymphocyte must receive two mandatory signals:
- Specific recognition: the TCR receptor and the CD8 coreceptor bind to the peptide-MHC-I complex on the APC.
- Costimulation: interaction of the CD28 molecule on the T-cell membrane with CD80/86 molecules on the APC surface.
Proliferation and T-helper help
Following successful activation, intensive proliferative clonal expansion begins, lasting 5–7 days. The main growth factor for lymphocytes at this stage is the cytokine IL-2.
If the stimulation during initial presentation was strong, CD8+ T cells synthesize enough IL-2 themselves to cover their needs (autocrine pathway). With a weak signal, they are in acute need of help from CD4+ T helpers. Helpers supply IL-2 in a paracrine manner and also secrete IFNγ, which additionally increases the density of MHC molecules on dendritic cells, enhancing the transmission of the activation signal. IL-7 and IL-15 can also act as reserve growth factors.
Differentiation and migration to the focus
In parallel with proliferation, cells differentiate into mature cytotoxic T lymphocytes (CTLs). Specialized granules containing killing proteins form in their cytoplasm: perforin, granzymes, and granulysin.
At this stage, the set of surface markers changes radically:
- The activation molecule CD45 undergoes splicing. Naive cells carry the full-length CD45RA form, while effectors and memory cells gradually lose exons, transitioning to the shortened CD45R0 form.
- Homing receptors change. T cells lose molecules that retain them in lymph nodes (CD62L, CCR7) and acquire integrins (e.g., VLA-4, LFA-1) and chemokine receptors (CCR4, CCR6). This allows them to directionally migrate into non-lymphoid barrier tissues and sites of inflammation.
Mechanisms of contact cytolysis
Upon encountering a target, the CTL forms a cytolytic immune synapse. At this stage, costimulation is no longer required — only the binding of the TCR receptor to the MHC-I molecule of the infected cell is sufficient. Killing is carried out by inducing apoptosis through two pathways:
- Perforin-granzyme pathway. Following cytoskeleton polarization, the T cell releases the granule contents into the synaptic cleft. In the presence of calcium ions, perforin forms pores in the target membrane. The protease granzyme B penetrates inside through these channels, cleaving caspase 3 and the Bid factor, triggering an irreversible cell death process.
- Fas-dependent apoptosis. The process of contact killing without granule exocytosis. Fas ligand on the T-cell membrane binds to the Fas receptor on the target, transmitting a direct intracellular signal to activate caspase 8.
As a result, the target cell dies and is neatly utilized by phagocytes. This prevents the development of an acute inflammatory reaction and saves surrounding healthy tissues from damage.
Briefly: answers to topical questions
Which cell types are capable of functioning as professional antigen-presenting cells for naive CD8+ lymphocytes?
Only dendritic cells are capable of functioning as professional antigen-presenting cells for naive CD8+ lymphocytes.
During the primary immune response, it is they that present the antigenic peptide as part of the MHC-I molecule. This is a mandatory condition for the primary activation of naive CD8+ T cells and their subsequent differentiation into mature cytotoxic T lymphocytes (killer T cells). Other professional APCs (macrophages and B lymphocytes) can effectively activate only pre-activated T cells (effectors and memory cells).
Which subpopulations of CD8+ memory T cells are formed after the immune response concludes?
Upon completion of the immune response, two main subpopulations of memory T cells are formed:
- Central memory T cells — retain the homing receptors of naive cells and constantly recirculate, returning to the T-cell zones of secondary lymphoid organs.
- Effector memory T cells — lose the ability to migrate into secondary lymphoid organs and head to barrier tissues, bone marrow, and inflammation sites.
Specific features of CD8+ memory T cells in particular are the absence of cytotoxic activity, absence of cytolytic granules, and lack of molecular-genetic manifestations (expression of perforin and granzyme B genes).
What mechanisms do viruses use to evade recognition by cytotoxic T lymphocytes?
To evade recognition by cytotoxic T lymphocytes, viruses use mechanisms that suppress the expression of MHC-I molecules on the surface of infected cells.
A decrease or cessation of MHC-I expression leads to impaired presentation of viral antigens and suppression of the CD8+ T lymphocyte response. In particular, such mechanisms are used by:
- Adenoviruses — selectively suppress MHC-I expression.
- Cytomegalovirus — suppresses the expression of MHC molecules of both classes.
Such a decrease in expression is an attempt by the mutated cell to "escape" from killer T cells, but this process is compensated for by the activation of natural killer (NK) cells.
The mnemonic APDC helps remember the 4 sequential stages of cytotoxic response development: Activation, Proliferation, Differentiation, Cytolysis.
Class and exam questions
Is costimulation required for a mature killer T cell to kill a target cell?
No, costimulation (via CD28 and CD80/86) is only needed at the stage of primary activation of a naive T lymphocyte. To carry out the effector function, specific recognition of the MHC-I-peptide complex is sufficient.
What is cross-presentation and why is it needed?
This is a mechanism whereby extracellular antigens are incorporated into MHC-I molecules rather than MHC-II. This is necessary so that a dendritic cell that has engulfed a virus, but is not itself infected by it, can activate naive CD8+ T cells.
Why does immune cytolysis not cause inflammation?
Cytotoxic T lymphocytes kill target cells exclusively by inducing apoptosis. Apoptotic cells are rapidly cleared by phagocytes before they disintegrate, so damage to healthy tissues does not occur.
What else to study on this topic
- Structural features of the MHC-I antigen-binding cleft (peptide size 8–10 amino acids)
- Comparative characteristics of immune cytolysis (CTLs) and natural cytolysis (NK cells)
- Alternative receptor pathway of apoptosis induction via tumor necrosis factor (TNFα)
- Molecular structure of the cytolytic synapse and the role of adhesion molecules (LFA-1, CD2)
- The phenomenon of killer T-cell recycling (multiple acts of cytolysis by a single cell)
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