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

Cell Immunol. 1998 Nov 25;190(1):51-60. doi: 10.1006/cimm.1998.1389.


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-beta 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 suppression in vivo in 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-beta Mab abolishes the effect of bystander suppression in vivo. We suggest that TGF-beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal
  • Antigens / administration & dosage
  • B-Lymphocytes / immunology
  • Cattle
  • Chickens
  • Dose-Response Relationship, Immunologic
  • Immunization
  • Insulin / administration & dosage
  • Insulin / genetics
  • Insulin / immunology
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / immunology
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Ovalbumin / administration & dosage
  • Ovalbumin / immunology
  • Self Tolerance / physiology*
  • Stem Cells / immunology
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / immunology*


  • Antibodies, Monoclonal
  • Antigens
  • Insulin
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-4
  • Ovalbumin