antigen-presenting cell

**Types** - Professional APCs: dendritic cells (DCs), macrophages, B cells. They constitutively express MHC II and costimulatory molecules (B7-1/CD80, B7-2/CD86), and are induced by infection or inflammation (e.g., via TLR signaling). - Dendritic cells are the most potent APCs and the key link between innate and adaptive immunity. They are the only APCs that prime naive T cells. Immature DCs in tissue (Langerhans cells in skin) capture antigen, then migrate via lymphatics to regional lymph node paracortex (T-cell zone), upregulating CCR7, MHC II, and B7. - Macrophages: phagocytose and present antigen. IFN-γ from Th1 cells further activates them (positive feedback). - B cells: bind antigen via surface Ig, internalize it, and present it to helper T cells. This is required for T-dependent B-cell activation, class switching, and affinity maturation (CD40–CD40L interaction). - Nonprofessional APCs: all nucleated cells (and platelets) express MHC I and present endogenous (cytosolic) antigens to CD8+ T cells. Some cells (e.g., endothelial cells, thymic epithelial cells) can express MHC II under certain conditions.

**MHC class I pathway (endogenous antigens: viral, tumor)** - Cytosolic proteins are degraded by the proteasome, and peptides are transported into the ER by TAP. - In the ER, peptides load onto MHC I (heavy chain plus β2-microglobulin), assisted by calnexin, calreticulin, tapasin, and ERAP. - The complex goes to the cell surface and is recognized by the TCR on CD8+ T cells (CD8 binds the α3 domain of MHC I). The result is cytotoxic killing. - Defects: TAP deficiency causes bare lymphocyte syndrome type I. Viruses (e.g., HSV, CMV) can inhibit TAP or downregulate MHC I, so NK cells (which detect "missing self") become important.

**MHC class II pathway (exogenous antigens)** - Extracellular antigen is endocytosed into a phagolysosome and degraded. - In the ER, MHC II (α and β chains) is made with the invariant chain (Ii), which blocks the peptide-binding groove. In the endosome, Ii is cleaved, leaving CLIP. HLA-DM exchanges CLIP for the antigenic peptide. - The complex goes to the cell surface and is recognized by the TCR on CD4+ T cells (CD4 binds the β2 domain of MHC II). - Defect: absent MHC II causes bare lymphocyte syndrome type II (CIITA or RFX mutations), leading to severe combined-like immunodeficiency with low CD4+ T cells.

**Cross-presentation** - DCs can present exogenous antigen on MHC I to activate CD8+ T cells. This matters for viral and tumor immunity and for vaccines.

**Signals required for T-cell activation** - Signal 1: TCR–peptide:MHC (CD4 or CD8 coreceptor assists). - Signal 2 (costimulation): B7 (CD80/86) on APC binds CD28 on T cell. Without it, the T cell becomes anergic. - Signal 3: cytokines (e.g., IL-12 from APCs promotes Th1 differentiation). - CTLA-4 (on T cells) binds B7 with higher affinity and downregulates the response (target of ipilimumab). PD-1 on T cells binds PD-L1 on APCs and tumor cells, causing inhibition (target of pembrolizumab and nivolumab). - Superantigens (e.g., TSST-1, staphylococcal enterotoxins) bind MHC II outside the peptide groove and the TCR Vβ region, causing nonspecific polyclonal T-cell activation and massive cytokine release (toxic shock syndrome).

**Clinical correlations** - MHC II–associated diseases: HLA-DR3 (SLE, Graves, type 1 DM, Sjögren), HLA-DR4 (rheumatoid arthritis, type 1 DM), HLA-DQ2/DQ8 (celiac disease), HLA-DR2 (MS, Goodpasture). - MHC I–associated diseases: HLA-B27 (seronegative spondyloarthropathies), HLA-A3 (hemochromatosis). - Transplant rejection: direct allorecognition occurs when donor APCs present to recipient T cells. HLA matching reduces rejection. - Follicular dendritic cells are not true APCs for T cells. They present antigen (as immune complexes) to B cells in germinal centers and do not express MHC II.

**High-yield mnemonics** - "MHC 1 × CD8 = 8 (1 × 8 = 8)" and "MHC 2 × CD4 = 8 (2 × 4 = 8)". - Class I = endogenous, ER loading with TAP, all nucleated cells. Class II = exogenous, endosome loading with HLA-DM and CLIP, APCs only.