Cover: Immunomodulatory effects of CpG DNA. Allergen is presented by dendritic cells to CD4⁺ T_H0 lymphocytes and may result in their differentiation into T_H2 cytokine-producing cells. IL-4, IL-13, and IL-5 regulate the asthmatic response. IL-4 directs the growth and differentiation of T cells toward a T_H2 cytokine profile. IL-4 and IL-13 regulate the synthesis of IgE by B cells. IL-5 regulates the differentiation and egress of eosinophils from the bone marrow into the blood. Tissue eosinophils and activated mast cells release a variety of inflammatory mediators that increase mucus production, airway edema, and smooth muscle contraction. In general, CpG DNA elicits T_H1-biased immune responses that prevent or reverse T_H2-mediated inflammation. CpG DNA activated pathways and critical mediator are shown in bold. CpG DNA-inhibited pathways are shown with dashed lines. ISS-ODN increase production of T_H1 cytokines IL-12, IL-18, interferon-{gamma}, and IL-6, and decreased production of T_H2 cytokines IL-4 and IL-5. T cells are inactivated by increased production of anti-inflammatory cytokines IL-10 and TGF-{beta}1 by dendritic and T regulatory (Tr) cells. B-cells proliferate and produce IgG2 antibody. NK cells are activated by IL-12 and IL-18. For more information see Perspective by Silverman and Drazen beginning on page 645. (Modified from Ref. 4 with permission.)