CD4 T cell

**Development and selection:** CD4 T cells arise from double-positive (CD4+CD8+) thymocytes in the thymic cortex. Positive selection (cortical epithelial cells) tests for MHC II recognition, which yields CD4+ cells. Negative selection (medullary epithelial cells and dendritic cells, with AIRE promoting self-antigen expression) deletes strongly self-reactive clones. AIRE mutations cause autoimmune polyendocrine syndrome type 1. Thymic aplasia (DiGeorge, 22q11.2 deletion) causes low T cell numbers.

**Activation (needs 2 signals):** - Signal 1: TCR binds peptide–MHC II on an antigen-presenting cell (dendritic cell, macrophage, B cell). CD4 acts as the co-receptor that binds MHC II (β2 domain). - Signal 2 (costimulation): CD28 on the T cell binds B7 (CD80/CD86) on the APC. Without signal 2, the T cell becomes anergic. - CTLA-4 binds B7 and inhibits activation (ipilimumab blocks it). PD-1 on T cells binds PD-L1 on tumor cells and inhibits activation (pembrolizumab and nivolumab block it). - Abatacept is a CTLA-4–Ig fusion protein that blocks costimulation (used in RA).

**Differentiation (cytokine-driven):** - **Th1:** Driven by IL-12 (from macrophages and dendritic cells). Transcription factor is T-bet. Secretes IFN-γ and IL-2. It activates macrophages (granuloma formation, intracellular pathogens such as mycobacteria) and drives delayed-type (type IV) hypersensitivity. IFN-γ inhibits Th2. Defects in the IL-12/IFN-γ axis cause disseminated mycobacterial infection. - **Th2:** Driven by IL-4. Transcription factor is GATA-3. Secretes IL-4, IL-5, IL-13. It drives B cell class switching to IgE (IL-4), eosinophil activation (IL-5), and IgA (IL-5). It mediates the response to helminths and type I hypersensitivity (allergy and asthma). IL-4 inhibits Th1. - **Th17:** Driven by TGF-β and IL-6 (IL-23 maintains them). Transcription factor is RORγt. Secretes IL-17, IL-21, IL-22. It recruits neutrophils and defends against extracellular bacteria and fungi. Defective Th17 cells cause **hyper-IgE syndrome (Job syndrome)**, a STAT3 mutation with recurrent cold (non-inflamed) staph abscesses, eczema, retained primary teeth, coarse facies, and high IgE. Chronic mucocutaneous candidiasis also involves Th17 defects. - **Treg:** Driven by TGF-β and IL-2. Markers are CD4, CD25, and FoxP3. Secretes IL-10 and TGF-β to maintain tolerance. FoxP3 mutation causes **IPEX** (immune dysregulation, polyendocrinopathy, enteropathy, X-linked). - **Tfh:** Provide B cell help in germinal centers (CD40L–CD40 interaction, IL-21).

**Key B cell help:** CD40L (CD154) on the T cell binds CD40 on the B cell, allowing class switching and affinity maturation. Defective CD40L causes **hyper-IgM syndrome** (X-linked): high IgM, low IgG/IgA/IgE, and recurrent pyogenic infections plus opportunistic infections such as Pneumocystis.

**Clinical significance:** - **HIV:** gp120 binds CD4 and the co-receptor CCR5 (macrophage-tropic, early infection) or CXCR4 (T cell–tropic, late infection). gp41 mediates fusion. Homozygous CCR5-Δ32 mutation confers resistance. Maraviroc blocks CCR5. Enfuvirtide blocks gp41. Progressive CD4 loss leads to opportunistic infections: <200 is AIDS-defining (PCP prophylaxis with TMP-SMX begins <200), <100 brings Toxoplasma (prophylaxis <100), <50 brings MAC (azithromycin prophylaxis <50 in older guidelines; current guidelines do not recommend it if ART is started immediately), CMV retinitis, and cryptococcal meningitis. The CD4:CD8 ratio inverts (normal ~2:1). - **Autoimmunity:** Th1 and Th17 cells are implicated in MS, type 1 diabetes, RA, psoriasis, and IBD (IL-23/IL-17 inhibitors treat psoriasis). - **Transplant:** Cyclosporine and tacrolimus inhibit calcineurin and therefore IL-2 transcription and T cell activation. Basiliximab blocks CD25 (the IL-2 receptor). - **Graft rejection:** CD4 cells recognize foreign MHC II (acute rejection and indirect pathway). - **Superantigens** (TSST-1, staphylococcal enterotoxins) cross-link MHC II and the TCR outside the antigen groove, causing polyclonal CD4 activation and a cytokine storm (toxic shock syndrome). - **Sarcoidosis:** CD4 predominant in lung (BAL CD4:CD8 is increased), with non-caseating granulomas.

**Mnemonic:** CD4 × MHC II = 8 (4 × 2 = 8). CD8 × MHC I = 8 (8 × 1 = 8).

**Surface markers:** CD3 (TCR complex, all T cells), CD4, TCR, CD28. Memory cells express CD45RO. Naive cells express CD45RA.