Differential regulation of protein- and polysaccharide-specific Ig isotype production in vivo in response to intact Streptococcus pneumoniae

Adaptive humoral immunity to extracellular bacteria is largely mediated by antibody specific for both protein and polysaccharide antigens. Proteins and polysaccharides are biochemically distinct, and as a result are processed differently by the immune system, leading to different mechanistic pathways for eventual elicitation of specific Ig isotypes. Much of our current knowledge concerning the parameters underlying anti-protein and anti-polysaccharide Ig responses have come from studies using soluble, purified antigens. However, the lessons learned from these studies are not entirely applicable to the mechanisms underlying physiologic anti-protein and anti-polysaccharide Ig responses to intact bacteria. Specifically, unlike isolated, soluble antigens, intact bacteria are complex particulate immunogens in which multiple protein and polysaccharide antigens, and bacterial adjuvants (e.g. Toll-like receptor ligands) are co-expressed, indeed often physically linked. In this review, data from a series of recent studies are discussed in which heat-killed, intact Streptococcus pneumoniae was used as an immunogen to study the mechanisms underlying in vivo anti-protein and anti-polysaccharide Ig isotype induction. An unexpected role for CD4(+) T cells and dendritic cells for induction of IgG anti-polysaccharide responses by intact bacteria is discussed, and shown to have distinct mechanistic features from those that mediate anti-protein responses. The further role of cytokines, Toll-like receptors, and B cell receptor signaling in mediating these responses, and its implications for the effectiveness of anti-pneumococcal, polysaccharide-based vaccines, is also discussed.