(A) The immune response is based on a series of immunological synapses with a common mechanism based on phosphatase exclusion. Innate leg: An intracellular pathogen infects cells, activating innate sensing mechanisms and leading to phagocytosis by an immature DC (iDC). This phagocytic synapse contributes to maturation of the DC (mDC). If the pathogen downregulates MHC class I in the infected cell, then the infected cell can be directly recognized by NK cells. Afferent leg: The mDC presents antigens on MHC class I to cytotoxic T cell precursors (CD8), on MHC class II to helper T cell precursors (CD4), and as intact complexes to B cells. Efferent leg: CTLs can directly kill MHC class I–positive infected cells, and the infected target induces cytokine production by the CD8 T cell. Helper T cells allow selection of high-affinity activated B cells and help B cells to generate an appropriate type of antibody. The B cell provides costimulatory molecules that promote cytokine production by the helper T cell. (B) The inflammatory reflex is based on innervation of a subset of helper T cells that express choline acetyltransferase. The vagus nerve relays signals to adrenergic neurons in the celiac ganglion that form neuroimmune synapses with the helper T cells. Adrenergic receptors on the T cell trigger production of acetylcholine (ACh), which interacts with cholinergic receptors on macrophages to suppress production of inflammatory cytokines such as TNF.