dendritic cell

**Origin and types** - Derived from bone marrow hematopoietic precursors (myeloid and lymphoid progenitors). - Conventional/myeloid DCs (cDC1, cDC2) are the main antigen presenters. cDC1 specialize in cross-presentation to CD8+ T cells. cDC2 mainly activate CD4+ T cells. - Plasmacytoid DCs (pDCs) produce large amounts of type I interferon (IFN-α/β) during viral infection. - Tissue-specific forms include Langerhans cells in the skin (Birbeck granules, S-100+, CD1a+) and dermal DCs. - Follicular DCs are NOT true hematopoietic APCs. They are stromal-derived cells in B-cell follicles that display antigen-antibody complexes to B cells (germinal center selection). They do not present antigen on MHC II to T cells.

**Function (stepwise)** 1. Immature DCs in peripheral tissues (skin, mucosa) sample antigen by phagocytosis, macropinocytosis, and receptor-mediated endocytosis. 2. Pattern recognition receptors (TLRs, C-type lectins) detect PAMPs. This triggers maturation. 3. Mature DCs upregulate CCR7, MHC II, and costimulatory molecules (B7-1/CD80, B7-2/CD86, CD40). They migrate through afferent lymphatics to the T-cell zones (paracortex) of lymph nodes. 4. Signal 1 is the peptide-MHC/TCR interaction. Signal 2 is B7 binding to CD28 on the T cell. Signal 3 is cytokines (e.g., IL-12 drives Th1 differentiation). 5. Antigen is presented on MHC II to CD4+ T cells (exogenous antigen). It is presented on MHC I to CD8+ T cells (endogenous antigen, or exogenous antigen by cross-presentation).

**Key points for boards** - DCs are the only APCs that can activate NAÏVE T cells, which is why they are the most effective APC. Macrophages and B cells mainly re-stimulate previously activated or memory T cells. - All APCs express MHC II: DCs, macrophages, B cells (plus thymic epithelial cells). All nucleated cells express MHC I. - Without costimulation (signal 2), T cells become anergic. This is a mechanism of peripheral tolerance, and tolerogenic DCs help maintain self-tolerance. - HIV: DCs (via DC-SIGN) bind gp120 and transport virus to lymph nodes, where CD4+ T cells are infected. Langerhans cells and DCs in mucosa are early targets. - Langerhans cell histiocytosis (LCH): clonal proliferation of Langerhans cells. Cells are S-100+, CD1a+, and show Birbeck granules ("tennis racket" shape) on EM. The BRAF V600E mutation is common. Presentations include Letterer-Siwe, Hand-Schüller-Christian (triad of lytic skull lesions, diabetes insipidus, exophthalmos), and eosinophilic granuloma. - Graft rejection: donor passenger DCs carry foreign MHC to the recipient and drive direct allorecognition, which is the main route of acute rejection. - Location in lymph node: DCs and T cells are in the paracortex. B cells and follicular DCs are in the follicles (cortex). Paracortex is underdeveloped in DiGeorge syndrome and in T-cell deficiencies. - Immunotherapy: Sipuleucel-T is an autologous DC-based vaccine for metastatic castration-resistant prostate cancer (activated with PAP-GM-CSF fusion protein). - Ralph Steinman won the 2011 Nobel Prize for discovering DCs.