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regulatory T cell

ImmunologyImmune systemHematologic/LymphaticGastrointestinalEndocrine

Summary

Regulatory T cells (Tregs) are CD4+ T cells expressing CD25 (IL-2 receptor α) and the transcription factor FOXP3 that suppress immune responses and maintain self-tolerance. They act via IL-10, TGF-β, IL-35, CTLA-4, and IL-2 consumption. FOXP3 mutation causes IPEX syndrome.

Detail

**Phenotype:** CD4+ CD25+ (IL-2Rα) FOXP3+ T cells. FOXP3 is the master transcription factor. Tregs depend on IL-2 for survival and expansion. Most arise in the thymus (natural/tTregs). Some are induced in the periphery (iTregs) by TGF-β plus IL-2 (and retinoic acid in gut mucosa).

**Function:** Tregs maintain peripheral tolerance and limit immune pathology. Mechanisms: - Secrete the inhibitory cytokines IL-10, TGF-β, and IL-35. - Express CTLA-4, which binds B7 (CD80/CD86) on APCs. This blocks CD28 co-stimulation and downregulates APC function. - Consume IL-2 through high CD25 expression, starving effector T cells ("IL-2 sink"). - Can induce cytolysis of effector cells (granzyme/perforin).

**Clinical correlations:** - **IPEX syndrome** (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked): loss-of-function FOXP3 mutation (X-linked recessive) causes absent or defective Tregs. Features include autoimmune enteropathy with severe diarrhea, type 1 diabetes, thyroiditis, eczema or dermatitis, and cytopenias. Presents in infancy. Treatment is HSCT. - **CD25 (IL-2Rα) deficiency** and **CTLA-4 haploinsufficiency** give similar immune dysregulation. - **Autoimmunity:** reduced Treg number or function contributes to SLE, MS, T1DM, and others. - **Cancer:** tumors recruit Tregs, which suppress antitumor immunity. Anti-CTLA-4 (ipilimumab) removes this brake and can cause immune-related adverse events such as colitis, dermatitis, hypophysitis, and hepatitis. - **Transplant tolerance and GVHD:** Tregs are protective, and Treg-based therapies are under investigation. - **Low-dose IL-2** preferentially expands Tregs and is being studied for autoimmune disease. - **Immunosuppressants:** calcineurin inhibitors (cyclosporine, tacrolimus) block IL-2 production and can impair Treg function. Sirolimus (mTOR inhibitor) spares or favors Tregs.

**Board pearls:** - CD4+, CD25+, FOXP3+ is the classic Treg identifier. - Th1 is driven by IL-12 (T-bet). Th2 by IL-4 (GATA-3). Th17 by IL-6 and TGF-β (RORγt). Treg by TGF-β and IL-2 (FOXP3). - IL-10 and TGF-β are the key anti-inflammatory cytokines. - Don't confuse IPEX (FOXP3, Tregs) with APECED/APS-1 (AIRE, central tolerance defect), which causes chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.

Sources

  • First Aid for the USMLE Step 1 (Immunology: Lymphoid structures, T-cell differentiation, Immunodeficiencies)
  • Robbins & Kumar Basic Pathology (Diseases of the Immune System)
  • Abbas, Lichtman & Pillai: Cellular and Molecular Immunology (Immunological Tolerance and Autoimmunity)
  • Pathoma (Immunology)
  • Sakaguchi S et al. Regulatory T cells and immune tolerance. Cell 2008

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