Cellular immunity is the T-lymphocyte-mediated arm of adaptive defence. T cells recognise peptide antigens displayed by major histocompatibility complex (MHC) molecules, then coordinate macrophages, B cells and inflammation or directly kill infected and abnormal cells. Cellular immunity is essential against viruses, intracellular bacteria, fungi, tumours and transplanted tissue, but excessive or misdirected T-cell activity causes delayed hypersensitivity, autoimmunity and tissue damage.
At a glance
- CD4 helper T cells: coordinate immune responses through cytokines and cell contact.
- CD8 cytotoxic T cells: kill infected, malignant or otherwise abnormal cells presenting antigen on MHC I.
- Regulatory T cells: suppress excessive responses and maintain self-tolerance.
- Recognition rule: T-cell receptors recognise peptide plus the correct MHC molecule, not free antigen alone.
- Clinical failure: severe viral, fungal and opportunistic infection, poor tumour surveillance and impaired vaccine responses.
Learning outcomes
The learner should be able to describe T-cell development and selection, explain MHC I and II antigen presentation, differentiate CD4 helper subsets, describe CD8 cytotoxic killing, explain T-cell memory and tolerance, and apply cellular-immunity concepts to infection, transplantation, autoimmunity and emergency care.
1. T-cell development and the T-cell receptor
1.1 Development in the thymus
T-cell precursors arise in bone marrow and mature in the thymus. T-cell receptor (TCR) genes rearrange to create a diverse repertoire. Positive selection preserves cells that can recognise self-MHC; negative selection removes strongly self-reactive cells. Surviving cells become mainly CD4 or CD8 single-positive T cells and leave as naive lymphocytes.
1.2 TCR–CD3 complex
The TCR recognises a peptide–MHC complex. CD3 transmits the activation signal, while CD4 or CD8 stabilises interaction with MHC II or MHC I. Co-stimulatory and cytokine signals determine whether the cell becomes an effector, memory or regulatory T cell.
2. Antigen presentation
| Feature | MHC class I | MHC class II |
|---|---|---|
| Expression | Most nucleated cells | Professional antigen-presenting cells: dendritic cells, macrophages and B cells |
| Antigen source | Intracellular/cytosolic proteins, including viral and tumour proteins | Extracellular proteins taken up by endocytosis/phagocytosis |
| Processing | Proteasome, TAP transport into endoplasmic reticulum and peptide loading | Endosomal processing and loading in vesicular compartments |
| Recognised by | CD8 cytotoxic T cells | CD4 helper T cells |
| Main outcome | Kill infected or abnormal target cell | Coordinate macrophages, B cells and inflammation |
Dendritic cells can cross-present selected extracellular antigens on MHC I to prime CD8 responses. Tumours and viruses may evade by reducing MHC expression or interfering with antigen processing.
3. T-cell activation
Naive T cells require three coordinated signals:
- Signal 1: TCR recognition of peptide–MHC.
- Signal 2: co-stimulation, especially CD28 binding B7 molecules on an activated antigen-presenting cell.
- Signal 3: cytokines that direct differentiation.
Antigen recognition without adequate co-stimulation can induce anergy or tolerance. Inhibitory checkpoints such as CTLA-4 and PD-1 restrain activation; tumours can exploit these pathways to evade immunity.
4. CD4 helper T-cell subsets
| Subset | Key cytokines/transcriptional drivers | Main functions and clinical associations |
|---|---|---|
| Th1 | IFN-gamma; T-bet | Activates macrophages and supports intracellular pathogen control; tuberculosis and granulomatous inflammation |
| Th2 | IL-4, IL-5, IL-13; GATA-3 | Eosinophils, IgE, mucus and helminth defence; allergy and asthma |
| Th17 | IL-17, IL-22; ROR-gamma-t | Neutrophil recruitment and mucosal barrier defence; fungal infection and autoimmune inflammation |
| T follicular helper | IL-21 and other signals; Bcl-6 | Germinal-centre B-cell help, class switching and affinity maturation |
| Regulatory T cell | IL-10, TGF-beta; FoxP3 | Suppresses autoreactive and excessive responses; tolerance and immune homeostasis |
Subsets are functional tendencies rather than completely isolated categories. Cytokine environments and tissue signals can alter phenotype and plasticity.
5. CD8 cytotoxic T cells
5.1 Activation and differentiation
Naive CD8 cells are primed by dendritic cells, often with CD4 help and inflammatory cytokines. They expand into armed cytotoxic T lymphocytes (CTLs) and memory cells. CTLs migrate to infected or tumour tissue and inspect MHC I–peptide complexes.
5.2 Killing mechanisms
- Perforin–granzyme pathway: perforin facilitates entry of granzymes, which activate target-cell apoptosis.
- Fas–Fas ligand pathway: Fas engagement activates death-receptor apoptosis.
- Cytokines: IFN-gamma and TNF can inhibit pathogens and alter local inflammation.
After delivering a lethal hit, a CTL can detach and kill another target. This precision limits collateral damage, but widespread infection or excessive CTL activity can destroy essential tissue.
6. Cellular immunity against different threats
| Threat | Dominant cellular response | Potential pathology |
|---|---|---|
| Virus-infected cells | CD8 CTLs, NK cells, type I interferons and CD4 help | Viral cytopathic injury plus immune-mediated tissue damage |
| Intracellular bacteria | Th1 IFN-gamma activation of macrophages | Granuloma, caseation and chronic inflammation |
| Fungi | Th1/Th17 responses, macrophages and neutrophils | Invasive disease in T-cell or neutrophil deficiency |
| Helminths | Th2, eosinophils, mast cells and IgE | Allergic-type tissue injury and airway inflammation |
| Tumour cells | CD8 CTLs, NK cells and helper cytokines | Immune escape, checkpoint exploitation and tumour progression |
| Transplanted tissue | Direct/indirect alloreactive T cells and antibodies | Acute or chronic rejection |
7. T-cell memory
After antigen clearance, most effector T cells die, while memory cells persist. Central memory cells circulate through lymphoid organs; effector memory cells patrol peripheral tissues; tissue-resident memory cells remain near portals of entry. On re-exposure, memory cells activate more rapidly and require less proliferation.
Memory can be protective, but it can also sustain chronic infection, autoimmune disease or transplant rejection. Antigenic variation and immune evasion can reduce protective memory.
8. Delayed-type hypersensitivity
Type IV hypersensitivity is T-cell mediated and typically appears 24–72 hours after antigen exposure. Th1 and Th17 cytokines recruit macrophages and neutrophils; CD8 cells may directly kill target cells. Examples include tuberculin skin reactions, contact dermatitis, granulomatous inflammation and some drug eruptions.
Severe cutaneous adverse reactions, such as Stevens–Johnson syndrome/toxic epidermal necrolysis, involve immune-mediated epithelial injury and are emergencies requiring immediate drug withdrawal and specialist care.
9. Granulomatous inflammation
Persistent intracellular pathogens or foreign material stimulate macrophages and T cells. Th1 cells release IFN-gamma, activating macrophages that form epithelioid cells and multinucleated giant cells. Granulomas contain but may not eradicate the cause. They occur in tuberculosis, some fungal infections, sarcoidosis, Crohn disease and foreign-body reactions.
10. T-cell immunodeficiency
10.1 Causes
- HIV infection, especially with falling CD4 count.
- Congenital thymic or combined immunodeficiency.
- Corticosteroids, chemotherapy, transplant medicines and biologic agents.
- Severe malnutrition, malignancy, ageing or critical illness.
10.2 Clinical pattern
Look for recurrent or severe viral, fungal, protozoal and opportunistic infection; persistent diarrhoea; chronic mucocutaneous candidiasis; unusual malignancy; poor response to live vaccines; and disseminated infection from normally low-virulence organisms.
11. Autoimmunity and transplantation
11.1 Autoimmunity
Failure of central or peripheral tolerance permits autoreactive T cells to survive. Molecular mimicry, bystander activation, epitope spreading and tissue injury can amplify disease. CD4 cytokines and CD8 cytotoxicity contribute to rheumatoid arthritis, type 1 diabetes, multiple sclerosis, inflammatory bowel disease and other conditions.
11.2 Transplant rejection
- Hyperacute rejection: pre-existing antibodies cause immediate vascular injury.
- Acute cellular rejection: T cells attack graft cells and vessels days to months after transplant.
- Chronic rejection: persistent immune injury causes vascular narrowing, fibrosis and gradual organ dysfunction.
- Graft-versus-host disease: donor T cells attack recipient tissues, especially skin, gut and liver.
12. Immune checkpoints and cancer therapy
CTLA-4, PD-1 and PD-L1 limit T-cell activation to protect normal tissue. Checkpoint-inhibitor medicines release these brakes against cancer but may cause immune-related adverse events such as colitis, hepatitis, pneumonitis, endocrinopathy, myocarditis or dermatitis. A patient receiving immunotherapy with new organ symptoms requires urgent assessment for immune toxicity as well as infection or tumour progression.
13. Investigations of cellular immunity
| Investigation | What it assesses | Limitation |
|---|---|---|
| Full blood count/lymphocyte count | Broad cell numbers | Does not prove functional competence |
| Flow cytometry | CD3, CD4, CD8, B and NK cell subsets | Requires interpretation with age and clinical context |
| HIV viral load/CD4 count | HIV burden and helper-cell status | CD4 varies with acute illness and treatment |
| Lymphocyte proliferation assays | Functional response to mitogens/antigens | Specialist test with technical variation |
| Interferon-gamma release assay | T-cell sensitisation to selected TB antigens | Cannot by itself distinguish latent from active TB |
| Histology/immunohistochemistry | Cellular infiltrates and tissue injury | Sampling and interpretation limitations |
14. Emergency relevance
Advanced HIV or T-cell deficiency
- Consider opportunistic pneumonia, meningitis, TB, cryptococcosis, CMV, oesophageal candidiasis and malignancy.
- Stabilise first, then obtain targeted microbiology and immune assessment.
Severe immune-mediated injury
- New blistering rash, mucosal erosions, hypoxia, diarrhoea or hepatitis may represent drug hypersensitivity or checkpoint toxicity.
- Stop suspected triggers and escalate urgently.
Transplant patient
- Fever or organ dysfunction may be infection, rejection or drug toxicity.
- Do not alter immunosuppression without specialist involvement unless following an emergency protocol.
15. Cases
Case 1: CD4 decline and pneumonia
A patient with untreated HIV develops progressive breathlessness and dry cough. Cellular immunodeficiency broadens the differential to opportunistic infections. Assess oxygenation urgently, obtain imaging and microbiology and start appropriate protocol-directed treatment.
Case 2: New diarrhoea on checkpoint therapy
A cancer patient receiving PD-1 blockade develops severe diarrhoea and hypotension. Evaluate infection, dehydration, perforation and immune-mediated colitis; treatment decisions require urgent oncology input.
Case 3: Granulomatous disease
A patient has chronic cough, weight loss and apical lesions. Th1-driven granulomas may contain TB but do not prove it; obtain microbiology and imaging and follow TB infection-control protocols.
16. Exam pearls
- CD4 cells coordinate; CD8 cells kill; Treg cells suppress.
- CD4 cells recognise peptide on MHC II; CD8 cells recognise peptide on MHC I.
- CTLs kill through perforin–granzyme and Fas–Fas ligand apoptosis.
- Th1 responses activate macrophages; Th2 supports IgE/eosinophils; Th17 supports mucosal neutrophil defence.
- Granulomas represent a containment strategy that can also cause tissue destruction.
- T-cell deficiency predisposes especially to viral, fungal, protozoal and opportunistic infections.
Quick self-test
- What are the three signals required for naive T-cell activation?
- How do CD4 and CD8 T cells differ in MHC recognition?
- Name two mechanisms used by cytotoxic T cells to kill targets.
- Why can T-cell deficiency cause severe fungal and viral disease?
- What is a granuloma and what role does Th1 immunity play?
Answers
- TCR recognition of peptide–MHC, co-stimulation and cytokine direction.
- CD4 cells recognise peptide on MHC II; CD8 cells recognise peptide on MHC I.
- Perforin–granzyme release and Fas–Fas ligand death-receptor apoptosis.
- T cells coordinate macrophages, cytotoxic killing, antiviral defence and immune memory; loss permits opportunistic infection.
- A granuloma is an organised macrophage-rich response to persistent antigen; Th1 IFN-gamma activates macrophages and supports containment.
References and further reading
- NCBI Bookshelf: T-cell-mediated immunity.
- NCBI Bookshelf: T-cell-mediated cytotoxicity.
- NCBI Bookshelf: T cells and MHC proteins.
- NIAID: Immune cells.
- Follow local HIV, TB, transplant, oncology, anaphylaxis and severe-cutaneous-adverse-reaction protocols.
