CorpusHuman Anatomy
Lymphatic & ImmuneCell

Helper T cell (CD4⁺)

Also known as: CD4 T cell, CD4+ T cell, T helper cell, Th cell, Th1, Th2, Th17, Tfh, follicular helper T cell, helper T lymphocyte

CD4⁺ T cells that recognise peptide on MHC class II and direct the immune response through cytokines and CD40 ligand, differentiating into subsets (Th1, Th2, Th17, Tfh, Treg) tailored to different classes of pathogen.

Adaptive Immune Response

Overview

Normal CD4 count≈ 500–1500 cells/µL
AIDS threshold< 200 cells/µL

Helper T cells are the "conductors" of adaptive immunity. A naive CD4 T cell is activated in the paracortex of a lymph node by a dendritic cell presenting peptide on MHC class II with co-stimulation. The cytokines present during activation (signal 3) switch on lineage-defining transcription factors that commit the cell to a subset with a signature cytokine profile:

Th1 — induced by IL-12 (from DCs and macrophages) and IFN-γ; transcription factor T-bet; secrete IFN-γ (and IL-2, TNF). They activate macrophages to kill intracellular microbes, help CD8 T cells and favour opsonising IgG subclasses. Defence against intracellular bacteria (mycobacteria), protozoa and viruses; drive type IV hypersensitivity and granulomas. Th2 — induced by IL-4 (and epithelial alarmins IL-25, IL-33, TSLP); GATA3; secrete IL-4 (IgE class switch), IL-5 (eosinophils) and IL-13 (mucus, smooth muscle). Defence against helminths; drive allergy and asthma. Th17 — induced by TGF-β + IL-6 (maintained by IL-23); RORγt; secrete IL-17 and IL-22, recruiting neutrophils and inducing epithelial antimicrobial peptides. Defence against extracellular bacteria and fungi (Candida, S. aureus) at barriers; drive psoriasis, spondyloarthritis and IBD. Tfh — induced by IL-6 and IL-21; Bcl-6; express CXCR5, enter follicles and provide CD40L and IL-21 to germinal-centre B cells. Treg — induced by TGF-β and IL-2; FOXP3; suppressive.

The subsets cross-regulate (IFN-γ inhibits Th2; IL-4 and IL-10 inhibit Th1), which can bias a response: in leprosy, a strong Th1 response produces tuberculoid disease with few bacilli, whereas a Th2-skewed response produces lepromatous disease with abundant bacilli.

Location

Lymph-node paracortex and follicles, splenic PALS, tissues; ≈ 40–50% of blood lymphocytes.

Parts & subdivisions

  1. Th1
    IL-12 → T-bet → IFN-γ: macrophage activation, intracellular pathogens, type IV hypersensitivity.
  2. Th2
    IL-4 → GATA3 → IL-4, IL-5, IL-13: helminths, IgE, eosinophils, allergy.
  3. Th17
    TGF-β + IL-6 (IL-23) → RORγt → IL-17, IL-22: neutrophils, extracellular bacteria and fungi, autoimmunity.
  4. Follicular helper (Tfh)
    IL-6/IL-21 → Bcl-6 → CXCR5, CD40L, IL-21: germinal-centre B-cell help.
  5. Regulatory (Treg)
    TGF-β + IL-2 → FOXP3 → IL-10, TGF-β, CTLA-4: suppression and tolerance.

Function

  • Activate macrophages (Th1) and help cytotoxic T cells.
  • Help B cells to produce high-affinity, class-switched antibody (Tfh, via CD40L and cytokines).
  • Recruit eosinophils, neutrophils and other effector cells appropriate to the pathogen.
  • "License" dendritic cells (CD40L–CD40) to prime CD8 T cells and generate CD8 memory.

Clinical significance

HIV and the CD4 count

HIV selectively destroys CD4 T cells; the absolute CD4 count (normal ≈ 500–1500 cells/µL) predicts the risk of opportunistic infection (< 200: Pneumocystis; < 100: toxoplasmosis, cryptococcus; < 50: CMV, Mycobacterium avium complex). Losing helper cells cripples both antibody and cell-mediated immunity.

Subset-specific diseases and drugs

Th17 deficiency (e.g. STAT3 loss-of-function — hyper-IgE/Job syndrome; IL-17 pathway defects) causes chronic mucocutaneous candidiasis and staphylococcal abscesses. Hyper-IgM syndrome results from CD40L deficiency. Biologics target subset cytokines: anti-IL-17 (secukinumab) and anti-IL-23 (risankizumab), anti-IL-12/23 (ustekinumab) in psoriasis and IBD; anti-IL-4Rα (dupilumab) in atopic dermatitis and asthma.

Mnemonics

Th1 vs Th2

Th1 fights the 1-celled (intracellular microbes) with IFN-γ and macrophages; Th2 fights the 2-big (worms) with IL-4, IL-5 and IL-13 — and causes allergy.

Test yourself

MHC class II molecules…
  1. Are expressed on all nucleated cells
  2. Present endogenous peptides to CD8 T cells
  3. Present exogenous peptides to CD4 T cells and are expressed mainly on antigen-presenting cells
  4. Consist of a heavy chain associated with β2-microglobulin

Answer: Present exogenous peptides to CD4 T cells and are expressed mainly on antigen-presenting cells

Class II (HLA-DP, -DQ, -DR; α and β chains) is expressed on dendritic cells, macrophages, B cells and thymic epithelium and presents peptides from endocytosed (exogenous) proteins to CD4 T cells. Class I (heavy chain + β2-microglobulin) is on all nucleated cells and presents to CD8 cells.

HIV enters CD4 T cells by binding of gp120 to CD4 and a co-receptor. AIDS is defined by a CD4 count below…
  1. 1000 cells/µL
  2. 500 cells/µL
  3. 350 cells/µL
  4. 200 cells/µL

Answer: 200 cells/µL

A CD4 count < 200 cells/µL (or an AIDS-defining illness) defines AIDS; this is the threshold for Pneumocystis pneumonia risk and co-trimoxazole prophylaxis. Normal counts are ≈ 500–1500 cells/µL.

More lymphatic & immune system questions

Compiled from standard anatomy and physiology references — see the Lymphatic & Immune System sources. For education only; not medical advice.