RESCUE OF SELF-REACTIVE B-CELLS BY PROVISION OF T-CELL HELP IN-VIVO

We have previously demonstrated that antigen-specific T cell help carl rescue mature Ig transgenic (Tg) hen egg lysozyme (HEL)-specific B ce lls from tolerance induction upon transfer into soluble HEL-expressing Tg hosts. Here we extend these findings by showing that T cell help c ould also rescue both immature and mature self-reactive B cells from r apid 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(- ) cells from the bone marrow of the same donors survived and prolifera ted when given help following transfer to a soluble or membrane HEL-ex pressing host. In other words, T cell help must be available relativel y soon after the antigen signal to prevent induction of tolerance. Con sistent with this interpretation, the stronger stimulus provided by me mbrane-bound antigen, which deletes immature B cells before they leave the bone marrow, did not afford an opportunity for T cell help to res cue tolerant immature bone marrow-derived B cells upon transfer in viv o. Nevertheless, these B cells were capable of responding to T cell he lp in vitro, which speaks against an immutable susceptibility of immat ure B cells to tolerance induction. Taken together, these data indicat e that the strength of the antigen signal and availability of T cell h elp ave the primary determinants of the fate of both immature and matu re B cells, consistent with the model proposed by Bretscher and Cohn m ore than 25 years ago.