- Email: [email protected]
M. H. Julius
MHC R E S T R I C T I O N IN T/B INTERACTIONS
107
M. It. Julius: - - To J. Sprent :
Bystander responses do occur in vivo, the stringency of our definition is confusing the issue. We agree that H-2 restricted T/B interactions in conditions of unlinked recognition are an in vitro artifact mediated by concentrations of elieiting antigen (that for which the T cell is specific) impossible to attain in vivo. Consider then the deliberate use of low concentrations of eliciting antigen in vitro and the finding that only pre-activated bystander B cells are induced/amplified. If one ignores the specificity of the response for the moment, this mode of B-cell amplification is seen both in vitro and in vivo, characterized by the large increase in total Ig-secreting cells accompanying all T-dependent B-cell responses. The specificity of this Ig, which comprises over 90% of the absolute Ig increment (both in vivo and in vitro), appears unrelated to the inducing antigen. Its most likely origin, in my opinion, is from B cells involved in previous antigen encounter, either environmental or self, which are in a state of activation, rendering them susceptible to further amplification mediated by lymphokines generated in the most current response. This would be a bystander response, the specificity of which reflects the recent antigen history of the animal. A more deliberate experiment which proves the point has been published (Cell. Immunol., 1978, 36, 151). When animals are immunized with antigen A and subsequently boosted with antigen B, a response to A is rescued. The critical point, which reflects a required state of activation of bystander B cells, limiting their expression under physiological conditions, is the timing of injection of B relative to A. The injection of B must be within a period consistent with A-specific cells not having reverted to the resting state. To D. C. Parker and H.-P. Tony :
Your two references supporting the lack of sIg involvement in the activation of resting B cells beyond that of focussing T-cell help were carelessly chosen. High antigen concentrations, sufficient to non-specifically coat B cells, must certainly perturb m a n y membrane structures including surface Ig. As the potential effects are impossible to analyse, the system does not lend itself to the problem addressed. The bridging experiments of Cammisuli et al. fall equally short of proving the point. No data is presented indicating t h a t the T/B interactions analysed are MHC-restrieted. Moreover, their use of primed and recently in situ boosted haptenspecific B cells is reminiscent of conditions rendering B cells susceptible to nonMHC-restrieted T-maerophage-derived signals (Eur. J. Immunol., 1982, 12, 592). - - To C. Martinez-A. et al. :
Your inability to detect in vitro bystander B-cell activation is not sutlicient evidence that the B cells in your assay are , small resting B ceils )) (Europ, J. lmmnnol., 1984, 14, 22). The proportion of T-dependent PFC you induce relative to LPS is identical to t h a t which we have obtained ( P N A S , 1982, 79, 1989). obviating your argument that we are analysing the activation requirements of a minority of B cells. W h y don't you fractionate your B cells so we might finally be able to compare data? The argument t h a t I-A-functions as a direct transducing molecule in B-cell activation, independent of slg or not, is an attractive one. How you expect to draw any conclusions from experiments involving anti-IA in combination with any concentration of LPS, coupled to anti-Ig no less, is beyond me.
107
M. It. Julius: - - To J. Sprent :
Bystander responses do occur in vivo, the stringency of our definition is confusing the issue. We agree that H-2 restricted T/B interactions in conditions of unlinked recognition are an in vitro artifact mediated by concentrations of elieiting antigen (that for which the T cell is specific) impossible to attain in vivo. Consider then the deliberate use of low concentrations of eliciting antigen in vitro and the finding that only pre-activated bystander B cells are induced/amplified. If one ignores the specificity of the response for the moment, this mode of B-cell amplification is seen both in vitro and in vivo, characterized by the large increase in total Ig-secreting cells accompanying all T-dependent B-cell responses. The specificity of this Ig, which comprises over 90% of the absolute Ig increment (both in vivo and in vitro), appears unrelated to the inducing antigen. Its most likely origin, in my opinion, is from B cells involved in previous antigen encounter, either environmental or self, which are in a state of activation, rendering them susceptible to further amplification mediated by lymphokines generated in the most current response. This would be a bystander response, the specificity of which reflects the recent antigen history of the animal. A more deliberate experiment which proves the point has been published (Cell. Immunol., 1978, 36, 151). When animals are immunized with antigen A and subsequently boosted with antigen B, a response to A is rescued. The critical point, which reflects a required state of activation of bystander B cells, limiting their expression under physiological conditions, is the timing of injection of B relative to A. The injection of B must be within a period consistent with A-specific cells not having reverted to the resting state. To D. C. Parker and H.-P. Tony :
Your two references supporting the lack of sIg involvement in the activation of resting B cells beyond that of focussing T-cell help were carelessly chosen. High antigen concentrations, sufficient to non-specifically coat B cells, must certainly perturb m a n y membrane structures including surface Ig. As the potential effects are impossible to analyse, the system does not lend itself to the problem addressed. The bridging experiments of Cammisuli et al. fall equally short of proving the point. No data is presented indicating t h a t the T/B interactions analysed are MHC-restrieted. Moreover, their use of primed and recently in situ boosted haptenspecific B cells is reminiscent of conditions rendering B cells susceptible to nonMHC-restrieted T-maerophage-derived signals (Eur. J. Immunol., 1982, 12, 592). - - To C. Martinez-A. et al. :
Your inability to detect in vitro bystander B-cell activation is not sutlicient evidence that the B cells in your assay are , small resting B ceils )) (Europ, J. lmmnnol., 1984, 14, 22). The proportion of T-dependent PFC you induce relative to LPS is identical to t h a t which we have obtained ( P N A S , 1982, 79, 1989). obviating your argument that we are analysing the activation requirements of a minority of B cells. W h y don't you fractionate your B cells so we might finally be able to compare data? The argument t h a t I-A-functions as a direct transducing molecule in B-cell activation, independent of slg or not, is an attractive one. How you expect to draw any conclusions from experiments involving anti-IA in combination with any concentration of LPS, coupled to anti-Ig no less, is beyond me.