Rescue of self-reactive B cells by provision of T cell help in vivo.
We have previously demonstrated that antigen-specific T cell help can rescue mature Ig transgenic (Tg) hen egg lysozyme (HEL)-specific B cells from tolerance induction upon transfer into soluble HEL-expressing Tg hosts. Here we extend these findings by showing that T cell help could also rescue both immature and mature self-reactive B cells from rapid deletion in response to high-avidity membrane-bound HEL. Moreover, although short-lived anergic peripheral B cells that had matured in the presence of soluble self antigen could not be rescued by provision of T cell help, a proportion of immature anergic IgM+ IgD- CD23- B cells from the bone marrow of the same donors survived and proliferated when given help following transfer to a soluble or membrane HEL-expressing host. In other words, T cell help must be available relatively soon after the antigen signal to prevent induction of tolerance. Consistent with this interpretation, the stronger stimulus provided by membrane-bound antigen, which deletes immature B cells before they leave the bone marrow, did not afford an opportunity for T cell help to rescue tolerant immature bone marrow-derived B cells upon transfer in vivo. Nevertheless, these B cells were capable of responding to T cell help in vitro, which speaks against an immutable susceptibility of immature B cells to tolerance induction. Taken together, these data indicate that the strength of the antigen signal and availability of T cell help are the primary determinants of the fate of both immature and mature B cells, consistent with the model proposed by Bretscher and Cohn more than 25 years ago.
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW, Australia.
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Cook
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Basten
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Fazekas de St Groth
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002645:Chickens; D006183:H-2 Antigens; D066298:In Vitro Techniques; D008211:Lymphocyte Cooperation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017634:Self Tolerance; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D001324:Autoantigens; D006183:H-2 Antigens; D011948:Receptors, Antigen, T-Cell; D009113:Muramidase