Immune response pathways activated by smallpox vaccines. Immunization with the smallpox vaccines elicits a cascading network of integrated immune pathways. Non-specific innate responses activated by pattern recognition receptors serve to inhibit initial viral replication and to activate antigen presenting cells in order to properly initiate adaptive immunity. Innate inflammatory cytokines and chemokines then attract effector lymphocytes into infected tissues. T helper cells supply necessary cytokines (IL-4, IL-5) and costimulatory signals (CD40L) for the B cell maturation, replication and isotype switching. T cell help (IL-2, IFNg) also promotes CTL activation, clonal expansion and effector function. VACV-specific T helper cells can also have direct lytic activity. B cells produce antibodies that agglutinate, opsonize, and neutralize viral particles, fix complement and allow for antibody dependent cell cytotoxicity (ADCC). Activated CD8 T cells lyse infected cells through perforin, granzymes, and through death receptors such as FasL. Cytokine secretion (IFNg, TNFa) by T lymphocytes can also have direct antiviral activity. Together humoral and adaptive responses halt viral replication, lyse infected cells, and remove viral particles from the host. Virus-specific lymphocyte numbers then contract to a small, long-lived memory population capable of rapidly responding to subsequent infection with VACV and more. Electron micrograph of vaccinia virus adapted from the Centers for Disease Control and Prevention Public Health Image Library, image #2143.