1. Identity and Core Task
- Cytotoxic T lymphocytes (CTLs) are conventional CD8⁺ T cells whose hallmark function is the selective destruction of host cells displaying foreign peptides on MHC class I.
- They normally act against virus-infected cells, intracellular bacteria or protozoa, malignant cells, and mismatched graft tissue.
- A fraction of CD4⁺ T cells can also acquire cytolytic properties, particularly in the elderly, but CD8⁺ CTLs are the main professional killers.
2. Developmental Pathway in the Thymus
- Origin: Common lymphoid progenitors leave the bone marrow for the thymus and become thymocytes.
- Double-negative stage (DN): Earliest thymocytes lack TCR/CD3, CD4, and CD8 (≈1–2 % of thymic cells).
- TCR gene rearrangement: Random assembly of V(D)J segments produces a unique αβ (or γδ) T-cell receptor.
- Positive selection (cortical epithelium)Tests whether new TCRs can recognize self-MHC molecules.
- Only those binding self-MHC weakly survive; others die of neglect.
- Negative selection (cortex and medulla)Thymocytes whose TCR binds self-peptide–MHC with high affinity are eliminated to prevent autoimmunity.
- Cortical and medullary epithelial cells plus medullary dendritic cells mediate deletion; costimulatory inputs can intensify this purge.
- Egress: Mature, naïve CD8⁺ T cells exit to secondary lymphoid organs (lymph nodes, spleen).
3. Antigen Recognition Architecture
- TCR interaction: CD8⁺ TCRs scan peptides (8-11 aa) bound to MHC-I on virtually all nucleated cells.
- MHC-I polymorphism: Variability within the peptide-binding groove dictates which peptides each allele can present, shaping CTL specificity across individuals.
- Complementarity-determining regions (CDRs)CDR3 on TCR α and β chains carries the greatest sequence diversity and primarily contacts the bound peptide.
- Minor conformational changes in the peptide can dramatically alter T-cell activation.
4. Activation of Naïve CD8⁺ T Cells
| Signal | Delivered by | Outcome if Absent | Notes |
|---|---|---|---|
| 1. TCR engagement | Peptide–MHC-I on dendritic cells | No activation | CD8 co-receptor stabilizes binding |
| 2. Costimulation | CD80/CD86 on DC ↔ CD28 on T cell | Anergy or deletion | CTLA-4 competes with CD28 to dampen responses |
| 3. Cytokines | IL-2, IL-12, type I IFNs | Sub-optimal differentiation | Shapes effector vs. memory fate |
- Dendritic cells are the only antigen-presenting cells that efficiently prime naïve CTLs.
- Cooperative help from Th1 cells (IL-2, IFN-γ, licensing of DCs) is essential for massive clonal expansion—up to 10³–10⁴-fold.
- Strong TCR signaling can override CTLA-4 inhibition, ensuring pathogen-specific CTLs are generated while autoreactive cells are held in check.
5. Effector Phase—Mechanisms of Target-Cell Elimination
-
- Lytic-granule pathway (rapid and dominant)Polarization: Microtubule-organizing center, Golgi, and granules reposition toward the immunological synapse.
- Perforin forms transmembrane pores.
- Granzymes enter through these pores; granzyme B activates caspases and nucleases, triggering apoptosis.
- Granulysin assists granzyme entry and has direct antimicrobial activity.
- Death-receptor pathway (slower, complementary)CTLs express FAS ligand (FASL) and TRAIL.
- Engagement of FAS (CD95) or TRAIL-R on the target triggers caspase–8–mediated apoptosis.
- FASL is supplied in two waves: pre-formed stores released within 15–30 min and newly synthesized FASL peaking ~2 h after strong activation—this second wave can cause bystander damage to nearby FAS⁺, uninfected cells.
- Cytokine secretionIFN-γ: up-regulates MHC-I, activates macrophages, and directly inhibits viral replication.
- TNF-α: synergizes with IFN-γ for tumor and pathogen control.
- IL-2: autocrine growth factor sustaining CTL proliferation.
Remarkably, a single CTL can kill a target displaying as few as 1–10 cognate peptide–MHC complexes.
6. Roles in Infection
- Viral diseases: High CTL activity correlates with rapid clearance; often oligoclonal responses where a handful of TCR clonotypes dominate.
- CTLs may also “cure” infected cells non-lytically by delivering sublethal granzyme doses or via cytokine-mediated suppression of viral replication—critical for preserving hepatocytes during hepatitis virus infection.
- Intracellular bacteria, fungi, parasites: Conventional CD8⁺ CTLs cooperate with unconventional cytotoxic subsets such as γδ T cells and MAIT cells; γδ T cells can kill without MHC restriction.
7. Memory Formation
| Subset | Homing pattern | Key traits |
|---|---|---|
| Tcm (central memory) | Lymph nodes & blood | High proliferative potential, IL-2 production |
| Tem (effector memory) | Peripheral tissues & blood | Rapid effector function, migrate to inflammation |
| Trm (tissue-resident memory) | Epithelia (gut, lung, skin, urogenital tract) | Stationed at barrier sites, ready for immediate protection |
- Generation of CD8⁺ memory requires CD4⁺ Th1 help during priming.
- IL-7 and IL-15 sustain memory numbers, driving homeostatic proliferation even without TCR stimulation (heterologous memory).
- Trm cells in skin are predominantly CD8⁺ in the epidermis, whereas dermis contains both CD4⁺ and CD8⁺ memory cells.
. Tumor Immunity and Transplantation
- Tumor control: CTLs, aided by Th1 cells and cytokines (IL-2, IL-27, IFN-γ), infiltrate and destroy cancer cells. A strong CD8⁺/Th1 gene signature predicts a favorable prognosis.
- Immune evasion: Tumours may down-regulate MHC-I or express FASL to kill attacking CTLs.
- CAR-T therapy: Genetically engineered T cells (usually CD8⁺) recognize tumor antigens without MHC, bypassing classical escape routes.
- Transplant rejection: Memory T cells, particularly heterologous memory generated by past infections, resist costimulation blockade, activate faster, and home to graft tissue—posing a greater threat than naïve T cells. Graft-versus-host disease after hematopoietic stem-cell transplantation is likewise driven by donor-derived alloreactive T cells.
9. Additional Points
- Functional subcategories of CTLs (Tc1, Tc2, Tc9, Tc17) are proposed based on cytokine profiles.
- NK cells, γδ T cells, and αβ CTLs constitute a cytotoxic continuum bridging innate and adaptive immunity.
- Severe combined immunodeficiencies (e.g., ZAP-70 deficiency) can abolish CD8⁺ T-cell development.
- Protein-energy malnutrition or micronutrient deficits (zinc, iron, vitamins) shrink the thymus and T-cell zones in lymph nodes, impairing T-cell immunity.
References
- Zagożdżon, R. (2023). Chapter 8: T Cell Activation. In: Gołąb, J. et al. (eds.), Immunology, pp. 139–154.
- Lasek, W. (2023). Chapter 9: Cytotoxic Mechanisms of Lymphocytes. In: Gołąb, J. et al. (eds.), Immunology, pp. 155–164.
- Jakóbisiak, M., Lasek, W., Gołąb, J. (2023). Chapter 10: Lymphocyte Populations and Subpopulations. In: Gołąb, J. et al. (eds.), Immunology, pp. 165–190.
- Głódkowska-Mrówka, E., & Stokłosa, T. (2023). Chapter 23: Immunodeficiencies. In: Gołąb, J. et al. (eds.), Immunology, pp. 429–435.
- Gołąb, J., Jakóbisiak, M., Nowis, D. (2023). Chapters 1 & 7: Introduction to Immunology and Development of Adaptive Immune Responses. In: Gołąb, J. et al. (eds.), Immunology.