The Function of TGF-β-Mediated Innocent Bystander Suppression Associated with Physiological Self-tolerancein Vivo

Innocent bystander suppression has been demonstrated in experimental models of transplantation tolerance and oral tolerance. This phenomenon is associated with expression of cytokines such as TGF-β or/and type II cytokines (e.g., IL-4, IL-10). However, the mechanism responsible for bystander suppression is poorly understood, as is its role in antigen-specific self-tolerance. Here, we describe a series of investigations using an antigen coimmunization strategy to examine the outcome of bystander suppressionin vivoin a well-characterized physiological model, using beef insulin transgenic (BI-Tg) mice, for self-tolerance. Our results demonstrate that: (1) T-cell-mediated 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-nonspecific (bystander suppression) when the self-antigen (BI) and a control antigen (chicken ovalbumin) are coadministered in BI-Tg mice; (2) bystander suppression is manifest as a local and transient, rather than a systemic and long-term, phenomenon; (3) bystander suppression is both time and antigen dose dependent; and (4) anti-TGF-β Mab abolishes the effect of bystander suppressionin vivo.We suggest that TGF-β-mediated innocent bystander suppression associated with physiological self-tolerance thus produces no major biological consequence for general immune responsiveness. It may prevent the activation of auto(or cross)-reactive lymphocytes.