T Cell Subsets and Functions
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Direct answer
T cell subsets are functionally distinct lymphocyte populations, identified by surface markers, transcription factors and the cytokines they secrete. CD4 helper cells differentiate into Th1, Th2, Th17 and regulatory T cells, each tuned to a different class of threat, while CD8 cytotoxic cells kill infected or malignant cells. Naive T cells need three signals from an antigen presenting cell before they become effectors.
What you must remember
- Th1 cells: IL-12-driven CD4 cells that depend on T-bet and secrete IFN-γ, which activates macrophages against intracellular pathogens such as Mycobacterium tuberculosis.
- Th2 cells: GATA-3-dependent cells secreting IL-4, IL-5 and IL-13, which drive IgE class switching, eosinophilia and defence against helminths.
- Th17 cells: RORγt-dependent cells producing IL-17 and IL-22, important against extracellular bacteria and fungi such as Candida.
- Regulatory T cells: CD4+ CD25+ FoxP3+ cells that suppress effector responses through IL-10, TGF-β and CTLA-4, with FoxP3 mutations causing IPEX syndrome.
- Cytotoxic T cells: CD8+ cells that recognise antigen on MHC class I and kill target cells through perforin and granzyme release.
- MHC restriction: CD4 cells recognise peptide on MHC class II, whereas CD8 cells recognise peptide on MHC class I.
- Co-stimulation: CD28 on the T cell binding B7 on the antigen presenting cell supplies the second signal that prevents anergy.
- Thymic selection: positive selection occurs in the cortex and negative selection in the medulla, where AIRE helps display tissue antigens to remove autoreactive clones.
From naive cell to effector: the differentiation pathway
A naive T cell does not pick a subset at random, because the cytokines around it at the moment of activation decide the fate. The steps below follow the sequence most textbooks use to explain it.
- Antigen recognition: a naive CD4 cell binds peptide on MHC class II of a dendritic cell through its T cell receptor, which provides the first signal.
- Co-stimulation: CD28 engages B7, supplying the second signal. Without it the T cell becomes anergic instead of expanding.
- Cytokine instruction: IL-12 from dendritic cells and macrophages pushes the cell towards Th1, IL-4 pushes it towards Th2, and IL-6 with TGF-β, sustained by IL-23, pushes it towards Th17.
- Lineage commitment: the instructing cytokines switch on master regulators, so T-bet marks Th1, GATA-3 marks Th2, RORγt marks Th17 and FoxP3 marks regulatory cells.
- Effector function: each committed cell secretes its signature cytokines and recruits the right effector cells, such as macrophages, eosinophils or neutrophils.
- Memory and contraction: most effector cells die once the antigen is cleared, and a smaller pool persists as memory cells for a faster secondary response.
Where the exam tries to catch you
Subset questions usually turn on which marker, cytokine or transcription factor goes with which lineage, so precise pairing wins marks.
- Trap: assuming CD4 and CD8 cells both recognise antigen on MHC class II Correct: CD4 cells use MHC class II and CD8 cells use MHC class I, which is why the marker tracks the helper or cytotoxic role.
- Trap: treating FoxP3 as a marker of Th17 cells Correct: FoxP3 identifies regulatory T cells, whereas RORγt identifies Th17 cells, so the transcription factor is the reliable label.
- Trap: linking IgE production to Th1 cells Correct: IL-4 from Th2 cells drives IgE switching, so Th2 is the subset behind allergy and helminth immunity.
Frequently asked questions
Which transcription factor defines Th17 cells?
RORγt defines Th17 cells, and it drives production of IL-17 and IL-22. Th17 cells are important against extracellular bacteria and fungi, and they are also linked to autoimmune inflammation when left unchecked.
Which cytokine pushes naive CD4 T cells towards the Th1 subset?
IL-12, released mainly by dendritic cells and macrophages, pushes naive CD4 T cells towards the Th1 subset. Th1 cells then secrete IFN-γ, which activates macrophages and supports killing of intracellular organisms such as Mycobacterium tuberculosis.
How do regulatory T cells suppress immune responses?
Regulatory T cells suppress immune responses through IL-10 and TGF-β, through consumption of IL-2 and through CTLA-4 signalling. Their development depends on FoxP3, so a FoxP3 mutation causes IPEX syndrome, a disorder of autoimmunity, enteropathy and endocrine failure.
Why do helper T cells carry the CD4 marker rather than CD8?
Helper T cells carry CD4 because CD4 binds MHC class II, which presents peptides from extracellular antigens to the T cell. Cytotoxic T cells carry CD8 instead, since CD8 binds MHC class I, the molecule that displays peptides from infected or malignant cells.