Zwitterionic polysaccharides (Zps) from pathogenic bacteria, such as Bacteroides fragilis, are virulence factors responsible for abscess formation associated with intra-abdominal sepsis. The underlying cellular mechanism for abscess formation requires T cell activation. Conversely, abscess formation can be prevented by prophylactic s.c. injection of purified Zps alone, a process also dependent on T cells. Hence, the modulatory role of T cells in abscess formation was investigated. We show that Zps interact directly with T cells with fast association/dissociation kinetics. Vβ repertoire analysis using RT-PCR demonstrates that Zps have broad Vβ usage. Zps-specific hybridomas responded to a variety of other Zps, but not to a nonzwitterionic polysaccharide, indicating cross-reactivity between different Zps. Furthermore, Zps-reactive T cell hybridomas could effectively transfer protection against abscess formation. Analysis of the proliferative capacity of T cells recovered from Zps-treated animals revealed that these T cells are anergic to subsequent stimulation by the different Zps or to alloantigens in an MLR. This anergic response was relieved by addition of IL-2. Taken together, the data show that this class of polysaccharides interacts directly with T cells in a nonbiased manner to elicit an IL-2-dependent anergic response that confers protection against abscess formation.