antigen-presenting cells

**Types** - Professional APCs: dendritic cells (most potent; link innate and adaptive immunity; Langerhans cells in skin are a subtype), macrophages, and B cells. Each expresses MHC II, MHC I, and costimulatory molecules. Thymic epithelial cells also express MHC II for T-cell selection. - Non-professional APCs: all nucleated cells present endogenous antigen on MHC I to CD8+ T cells. Most do not express MHC II unless induced, for example by IFN-γ.

**Antigen processing and presentation** - MHC II (exogenous antigen): 1. The APC phagocytoses or endocytoses the antigen. 2. The antigen is degraded in the endolysosome. 3. In the endoplasmic reticulum, the invariant chain (Ii) blocks the MHC II groove. In the acidified endosome, Ii is cleaved, leaving CLIP in the groove. 4. HLA-DM exchanges CLIP for the antigenic peptide. 5. The MHC II–peptide complex is displayed on the cell surface and recognized by the TCR on CD4+ helper T cells. CD4 binds the MHC II β2 domain. - MHC I (endogenous or cytosolic antigen, such as viral or tumor proteins): 1. The proteasome degrades the protein. 2. TAP transports peptides into the ER. 3. Peptides load onto MHC I, assisted by calnexin, calreticulin, and tapasin, and β2-microglobulin stabilizes the complex. 4. The complex is displayed to CD8+ cytotoxic T cells. CD8 binds the MHC I α3 domain. - Cross-presentation: dendritic cells can present exogenous antigen on MHC I to activate naive CD8+ T cells. This matters for antiviral and antitumor immunity.

**T-cell activation requires two signals** - Signal 1: TCR binds the peptide–MHC complex. - Signal 2 (costimulation): B7 (CD80/CD86) on the APC binds CD28 on the T cell. - Signal 1 without signal 2 causes anergy. - CTLA-4 on T cells binds B7 with higher affinity and inhibits activation. Ipilimumab blocks CTLA-4 and is used in melanoma. Abatacept is a CTLA-4–Ig fusion protein that blocks B7, and is used in rheumatoid arthritis. - CD40 on the APC binds CD40L (CD154) on the helper T cell. This drives APC IL-12 production, B-cell class switching, and macrophage activation. CD40L defect causes hyper-IgM syndrome (X-linked). - Th1 differentiation is driven by IL-12 from the APC. APC IL-12 and IFN-γ promote Th1, and IL-4 promotes Th2.

**Clinical correlates** - MHC II deficiency (bare lymphocyte syndrome) causes absent CD4+ T-cell responses and severe combined immunodeficiency-like disease. - MHC I deficiency (TAP defect) causes recurrent respiratory bacterial infections and reduced CD8+ T cells. - HLA associations: - HLA-DR3: type 1 DM, SLE, Graves disease, Hashimoto thyroiditis. - HLA-DR4: rheumatoid arthritis, type 1 DM. - HLA-B27: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, IBD-associated arthritis. - HLA-DQ2/DQ8: celiac disease. - Superantigens (TSST-1, staphylococcal enterotoxins) cross-link MHC II on APCs with the TCR Vβ region outside the antigen-binding groove. This polyclonally activates T cells and causes a cytokine storm (toxic shock syndrome). - Graft rejection: donor APCs present donor MHC to host T cells (direct pathway). Host APCs present processed donor antigen (indirect pathway). - B cells act as APCs when they internalize antigen via their BCR and present it on MHC II to helper T cells. This allows T-cell help for class switching and affinity maturation. - Dendritic cells in skin and mucosa capture antigen, migrate via lymphatics to regional lymph node paracortex (T-cell zone), and activate naive T cells. Maturation upregulates MHC II and B7. Follicular dendritic cells are not true MHC II APCs. They display intact antigen to B cells in germinal centers.

**High-yield mnemonic** "Class 1 vs 2: Rule of 8" – MHC I × CD8 = 8 (1 × 8 = 8); MHC II × CD4 = 8 (2 × 4 = 8).