The capsular polysaccharides (CPSs) of most pathogenic bacteria are T cell–independent antigens whose conjugation to carrier proteins evokes a carbohydrate-specific response eliciting T cell help. However, certain bacterial CPSs, known as zwitterionic polysaccharides (ZPSs), activate the adaptive immune system through processing by antigen-presenting cells and presentation by the major histocompatibility complex class II pathway to CD4+ T cells. This discovery was the first mechanistic insight into how carbohydrates—a class of biological molecules previously thought to be T cell independent—can in fact activate T cells. Through their ability to activate CD4+ T cells, ZPSs direct the cellular and physical maturation of the developing immune system. In this review, we explore the still-enigmatic relations between CPSs and the adaptive immune machinery at the cellular and molecular levels, and we discuss how new insights into the biological impact of ZPSs expand our concepts of the role of carbohydrates in microbial interactions with the adaptive immune system.
