Transforming growth factor beta and CD25 are important for controlling systemic dissemination following Yersinia enterocolitica infection of the gut.

Infection of the gut by invasive bacterial pathogens leads to robust inflammatory responses that if left unchecked can lead to autoimmune disease and other sequelae. How the immune system controls inflammation and limits collateral damage to the host during acute bacterial infection is poorly understood. Here, we report that antibody-mediated neutralization of transforming growth factor beta (TGF-beta) prior to infection with the model enteric pathogen Yersinia enterocolitica reduces the mean time to death by 1 day (P=0.001), leads to rapid colonization of the liver and lung, and is associated with exacerbation of inflammatory histopathology. During Yersinia enterocolitica infection CD4+ cells are the source of de novo TGF-beta transcription in the Peyer's patches, mesenteric lymph nodes, and spleen. Correspondingly there is both antigen-specific and -independent expansion of CD4+ CD25+ Foxp3+ and TGF-beta+ T-regulatory cells (T-regs) after Yersinia infection that is reduced in ovalbumin T-cell receptor-restricted OT-II mice. Functional inactivation of CD25 by anti-CD25 treatment results in more rapid death, dissemination of the bacteria to the liver and lungs, and exacerbated inflammatory histopathology, similar to what is seen during TGF-beta neutralization. Altogether, these data suggest that TGF-beta produced by T-regs is important in restricting bacteria during the acute phase of invasive bacterial infection of the gut. These data expand the roles of T-regs to include tempering inflammation during acute infection in addition to the well-established roles of T-regs in chronic infection, control of immune homeostasis, and autoimmune disease.