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Rescue of self-reactive B cells by provision of T cell help in vivo.

Cook MC, Basten A, Fazekas de St Groth B - Eur. J. Immunol. (1998)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW, Australia.

ABSTRACT
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.

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Summary of adoptive transfer experiments. (a) Experimental protocol for rescuing self-reactive B cells by means of antigen-specific T cell help. (b) Relative number of splenic H-2bk (gray bars) and H-2b (black bars) B cells 1 day after adoptive transfer. Values are normalized to the number of H-2b B cells detected in the spleen on day 1 for each particular experiment. (c) Relative number of H-2bk (gray bars) and H-2b (black bars) splenic B cells 3 days after adoptive transfer. Values are normalized to the number of H-2b B cells on day 1. (d) Ratio of H-2bk to H-2b splenic B cells 1 day (black bars) and 3 days (gray bars) after adoptive transfer. The experiments summarized in (b–d) are numbered according to the order in which they are described in the text.
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fig01: Summary of adoptive transfer experiments. (a) Experimental protocol for rescuing self-reactive B cells by means of antigen-specific T cell help. (b) Relative number of splenic H-2bk (gray bars) and H-2b (black bars) B cells 1 day after adoptive transfer. Values are normalized to the number of H-2b B cells detected in the spleen on day 1 for each particular experiment. (c) Relative number of H-2bk (gray bars) and H-2b (black bars) splenic B cells 3 days after adoptive transfer. Values are normalized to the number of H-2b B cells on day 1. (d) Ratio of H-2bk to H-2b splenic B cells 1 day (black bars) and 3 days (gray bars) after adoptive transfer. The experiments summarized in (b–d) are numbered according to the order in which they are described in the text.

Mentions: It was shown previously that naive anti-HEL Tg B cells destined to become tolerant upon exposure to sHEL in vivo could be rescued and induced to differentiate and secrete antibody by provision of T cell help in the form of activated T cells from H-2bk TCR Tg mice specific for moth cytochrome c peptide 87–103 (MCC87–103) in the context of I-Ek [12]. To control for possible antigen nonspecific effects of co-transferring activated T cells, all recipients were given activated H-2bk T cells, together with either purified H-2bk B cells with the capacity to present the appropriate peptide, H-2b B cells that could not do so, or a mixture of the two (Fig. 1a). For focussing peptide to B cell MHC, one of two methods of comparable efficacy were used, i.e. in vivo administration of a fusion protein expressing both HEL and MCC87–103 epitopes (HELcyt [15]), or pulsing of purified B cells with MCC87–103in vitro before transfer [12].


Rescue of self-reactive B cells by provision of T cell help in vivo.

Cook MC, Basten A, Fazekas de St Groth B - Eur. J. Immunol. (1998)

Summary of adoptive transfer experiments. (a) Experimental protocol for rescuing self-reactive B cells by means of antigen-specific T cell help. (b) Relative number of splenic H-2bk (gray bars) and H-2b (black bars) B cells 1 day after adoptive transfer. Values are normalized to the number of H-2b B cells detected in the spleen on day 1 for each particular experiment. (c) Relative number of H-2bk (gray bars) and H-2b (black bars) splenic B cells 3 days after adoptive transfer. Values are normalized to the number of H-2b B cells on day 1. (d) Ratio of H-2bk to H-2b splenic B cells 1 day (black bars) and 3 days (gray bars) after adoptive transfer. The experiments summarized in (b–d) are numbered according to the order in which they are described in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260656&req=5

fig01: Summary of adoptive transfer experiments. (a) Experimental protocol for rescuing self-reactive B cells by means of antigen-specific T cell help. (b) Relative number of splenic H-2bk (gray bars) and H-2b (black bars) B cells 1 day after adoptive transfer. Values are normalized to the number of H-2b B cells detected in the spleen on day 1 for each particular experiment. (c) Relative number of H-2bk (gray bars) and H-2b (black bars) splenic B cells 3 days after adoptive transfer. Values are normalized to the number of H-2b B cells on day 1. (d) Ratio of H-2bk to H-2b splenic B cells 1 day (black bars) and 3 days (gray bars) after adoptive transfer. The experiments summarized in (b–d) are numbered according to the order in which they are described in the text.
Mentions: It was shown previously that naive anti-HEL Tg B cells destined to become tolerant upon exposure to sHEL in vivo could be rescued and induced to differentiate and secrete antibody by provision of T cell help in the form of activated T cells from H-2bk TCR Tg mice specific for moth cytochrome c peptide 87–103 (MCC87–103) in the context of I-Ek [12]. To control for possible antigen nonspecific effects of co-transferring activated T cells, all recipients were given activated H-2bk T cells, together with either purified H-2bk B cells with the capacity to present the appropriate peptide, H-2b B cells that could not do so, or a mixture of the two (Fig. 1a). For focussing peptide to B cell MHC, one of two methods of comparable efficacy were used, i.e. in vivo administration of a fusion protein expressing both HEL and MCC87–103 epitopes (HELcyt [15]), or pulsing of purified B cells with MCC87–103in vitro before transfer [12].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW, Australia.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus