Treg

**Definition/Markers:** Regulatory T cells are a CD4+ T-cell subset defined by CD4+, CD25+ (high-affinity IL-2 receptor α chain), and FOXP3 (master transcription factor). They are generated in the thymus (natural/tTregs) or induced in the periphery (iTregs) from naive CD4+ T cells in the presence of TGF-β, IL-2, and retinoic acid (e.g., gut mucosa).

**Differentiation logic (high-yield):** TGF-β + IL-2 → Treg (FOXP3). TGF-β + IL-6 (± IL-23, IL-1) → Th17 (RORγt). IL-12 → Th1 (T-bet). IL-4 → Th2 (GATA-3).

**Mechanisms of suppression:** - Secrete inhibitory cytokines: IL-10, TGF-β, and IL-35. - CD25 acts as an IL-2 "sink," depriving effector T cells of IL-2 (Tregs depend on IL-2 but do not make much of it). - CTLA-4 on Tregs binds B7 (CD80/CD86) on APCs, blocking CD28 costimulation and downregulating APC function. - Can induce cytolysis of effector cells through granzyme/perforin.

**Clinical significance:** - **IPEX syndrome:** X-linked FOXP3 mutation → absent or dysfunctional Tregs. Presents in infancy with autoimmune enteropathy (severe watery diarrhea), type 1 diabetes/endocrinopathy (neonatal DM, thyroiditis), and eczematous dermatitis. Elevated IgE and eosinophilia are common. Treatment: HSCT, immunosuppression. - **CD25 (IL-2Rα) deficiency** and **CTLA-4 haploinsufficiency** give related immune dysregulation phenotypes. - **Autoimmunity:** Reduced or dysfunctional Tregs are implicated in SLE, MS, T1DM, and RA. - **Transplant tolerance/GVHD:** Treg expansion is protective. Low-dose IL-2 expands Tregs preferentially and is being studied in GVHD and autoimmunity. - **Cancer:** Tumors recruit Tregs and use them to evade immune surveillance. High intratumoral Tregs generally correlate with poor prognosis. Anti-CTLA-4 therapy (ipilimumab) enhances antitumor immunity by blocking CTLA-4 and can cause immune-related adverse events (colitis, hypophysitis, dermatitis, hepatitis). - **Pharmacology:** Basiliximab (anti-CD25) blocks the IL-2 receptor on activated T cells (transplant rejection prophylaxis) and can affect Tregs. Calcineurin inhibitors (cyclosporine, tacrolimus) reduce IL-2 production, which can impair Treg homeostasis. Abatacept (CTLA-4-Ig) mimics CTLA-4 inhibitory signaling. - **Peripheral tolerance:** Tregs are a key mechanism of peripheral tolerance, complementing central tolerance (thymic negative selection through AIRE-mediated self-antigen expression) and anergy.

**Board pearls:** CD4+/CD25+/FOXP3+ = Treg. FOXP3 mutation = IPEX. Think "TGF-β and IL-10 = anti-inflammatory." Tregs maintain tolerance to self and to gut commensals.