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 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.
Teng
Y T
YT
Department of Microbiology & Immunology, the University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Gorczynski
R M
RM
Hozumi
N
N
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal; D000941:Antigens / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology; D002417:Cattle; D002645:Chickens; D004306:Dose-Response Relationship, Immunologic; D007114:Immunization; D007328:Insulin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017634:Self Tolerance / Q000502:physiology*; D013234:Stem Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000941:Antigens; D007328:Insulin; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D010047:Ovalbumin