The function of TGF-beta-mediated innocent bystander suppression associated with physiological self-tolerance in vivo

Innocent bystander suppression has been demonstrated in experimental models of transplantation tolerance and oral tolerance, This phenomenon is associ ated with expression of cytokines such as TGF-beta or! and type II cytokine s (e.g,, IL-4, IL-10), However, the mechanism responsible for bystander sup pression is poorly understood, as is its role in antigen-specific self-tole rance. Here, we describe a series of investigations using an antigen coimmu nization strategy to examine the outcome of bystander suppression in vivo i n a web-characterized physiological model, using beef insulin transgenic (B I-Tg) mice, for self-tolerance, Our results demonstrate that: (1) T-cell-me diated peripheral hyporesponsiveness, or CD4(+) regulatory type II Th cell- mediated adoptive transfer of peripheral hyporesponsiveness (defined by an ELISA antibody assay), is antigen-specific at induction but effector-nonspe cific (bystander suppression) when the self-antigen (BI) and a control anti gen (chicken ovalbumin) are coadministered in BI-Tg mice; (2) bystander sup pression is manifest as a local and transient, rather than a systemic and l ong-term, phenomenon; (3) bystander suppression is both time and antigen do se dependent; and (4) anti-TGF-beta Mab abolishes the effect of bystander s uppression in vivo. We suggest that TGF-beta-mediated innocent bystander su ppression associated with physiological self-tolerance thus produces no maj or biological consequence for general immune responsiveness. It may prevent the activation of auto(or cross)-reactive lymphocytes, (C) 1998 Academic P ress.