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Coutinho: round 3
seminars in IMMUNOLOGY, Vol. 12, 2000: pp. 319–320 doi: 10.1006/smim.2000.0247, available online at http://www.idealibrary.com on
Coutinho: round 3
Response to Langman and Cohn
control CTL function. On the other hand, since regulatory T cells actually prevent graft infiltration by recipient lymphocytes, I would not ascertain at which step along the process of activation of CTLprecursors they operate. (b) The mechanisms for the recruitment of ‘second-order’ regulatory tissuespecific T cells in the periphery by regulatory selfspecific T cells that had been activated on TE are yet unclear, except for the relevant observation that such process is (self-)antigen-dependent. The peripheral pool of regulatory T cells is fed from new thymic emigrants with the relevant (self-)tissue-specificity. The whole process is postulated to involve ‘associative recognition’ on presenting cells that express both types of antigens, respectively recognized by the recruiter and the recruittee. The important aspect here is that ‘first-order’ regulatory T cells exit the thymus only after they have been activated, by selfreactivity of course. This actually lets the model be free of the old problem of the first ‘effector cell’ in the ‘two-signal model’. The model needs not to invoke particular ‘processing mechanisms’ to separate self from nonself: the issue is too important and TCR-specific to leave it to the general biochemistry of ‘processing mechanisms’. The model explains responsiveness to nonself by the known population dynamics of thymic emigrants, together with the observation that peripheral T cells, if kept resting (because they do not find specific antigen that is nonself), become refractory to regulatory recruitment with time after thymic emigration. In addition, the model adds that ‘professional APCs’ are capable of intrathymic deletion of would-be regulatory T cells (selected and activated on TE). Hence, regulation is expected to operate poorly for antigens presented on ‘professional APCs’, particularly if activated, be these self or nonself, as supported by a multitude of observations. (c) Regulatory T cells regulate autoreactive B cells by recognition of self peptides processed from the binding and internalization of (soluble) self-proteins, assuming that multivalent cell-surface antigens mediate deletion of B cells in bone marrow. I do not pos-
1. My statement that ‘TE and HC induce tolerance to antigens they do not express’ is the only alternative I can see to the unlikely assumption that those two types of cells express the relevant self-antigens from all other tissues. Thus, life-long tolerance can be experimentally ascertained to a variety of tissue grafts of donor origin. The model I reviewed here readily explains how this is achieved: (1) regulatory T cells are activated on TE to peptides that are shared by TE and all other tissues; (2) in the periphery, such ‘first-order’ regulatory T cells recruit into similar regulatory functions recent thymic emigrants with specificity for tissue-specific peptides. Evidence for such a mechanism has been produced: these peripherally recruited ‘second-order’ regulatory T cells were shown to ensure dominant tolerance in a tissue-specific manner, in contrast to the former that transfer tolerance to all grafts tested. 2. First, I do not agree with your designation of ‘suppressor’ T cells for the cells that we and others have demonstrated to be the mediators of dominant tolerance. One simple reason should be enough to justify my position: these cells do not suppress and actually participate in the stimulation to similar regulatory functions of recent thymic emigrants with self tissue-specificity. I am not at all sure that your synopsis of my model is ‘roughly correct’. In addition, I do not agree that ‘all the aggressive classes of T cells’ (CTL, for example) can be generated ‘near birth’. In any case I make the following comments. (a) I did postulate in the paper a role for regulatory T cells in the expression of the autoreactive B cell function; I did not address CTLs, but as such cells are systematically activated along with graft rejection and the fact that regulatory T cells impose graft tolerance, I would think that these do also
c
2000 Academic Press 1044–5323 / 00 / 030319+ 02 / $35.00 / 0
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Coutinho: round 3
tulate that regulatory T cells recognize antigens that are common to all B cells and therefore I do not see where there is the problem with ‘generalized suppression’ of B cells responses to nonself antigens.
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Coutinho: round 3
Response to Langman and Cohn
control CTL function. On the other hand, since regulatory T cells actually prevent graft infiltration by recipient lymphocytes, I would not ascertain at which step along the process of activation of CTLprecursors they operate. (b) The mechanisms for the recruitment of ‘second-order’ regulatory tissuespecific T cells in the periphery by regulatory selfspecific T cells that had been activated on TE are yet unclear, except for the relevant observation that such process is (self-)antigen-dependent. The peripheral pool of regulatory T cells is fed from new thymic emigrants with the relevant (self-)tissue-specificity. The whole process is postulated to involve ‘associative recognition’ on presenting cells that express both types of antigens, respectively recognized by the recruiter and the recruittee. The important aspect here is that ‘first-order’ regulatory T cells exit the thymus only after they have been activated, by selfreactivity of course. This actually lets the model be free of the old problem of the first ‘effector cell’ in the ‘two-signal model’. The model needs not to invoke particular ‘processing mechanisms’ to separate self from nonself: the issue is too important and TCR-specific to leave it to the general biochemistry of ‘processing mechanisms’. The model explains responsiveness to nonself by the known population dynamics of thymic emigrants, together with the observation that peripheral T cells, if kept resting (because they do not find specific antigen that is nonself), become refractory to regulatory recruitment with time after thymic emigration. In addition, the model adds that ‘professional APCs’ are capable of intrathymic deletion of would-be regulatory T cells (selected and activated on TE). Hence, regulation is expected to operate poorly for antigens presented on ‘professional APCs’, particularly if activated, be these self or nonself, as supported by a multitude of observations. (c) Regulatory T cells regulate autoreactive B cells by recognition of self peptides processed from the binding and internalization of (soluble) self-proteins, assuming that multivalent cell-surface antigens mediate deletion of B cells in bone marrow. I do not pos-
1. My statement that ‘TE and HC induce tolerance to antigens they do not express’ is the only alternative I can see to the unlikely assumption that those two types of cells express the relevant self-antigens from all other tissues. Thus, life-long tolerance can be experimentally ascertained to a variety of tissue grafts of donor origin. The model I reviewed here readily explains how this is achieved: (1) regulatory T cells are activated on TE to peptides that are shared by TE and all other tissues; (2) in the periphery, such ‘first-order’ regulatory T cells recruit into similar regulatory functions recent thymic emigrants with specificity for tissue-specific peptides. Evidence for such a mechanism has been produced: these peripherally recruited ‘second-order’ regulatory T cells were shown to ensure dominant tolerance in a tissue-specific manner, in contrast to the former that transfer tolerance to all grafts tested. 2. First, I do not agree with your designation of ‘suppressor’ T cells for the cells that we and others have demonstrated to be the mediators of dominant tolerance. One simple reason should be enough to justify my position: these cells do not suppress and actually participate in the stimulation to similar regulatory functions of recent thymic emigrants with self tissue-specificity. I am not at all sure that your synopsis of my model is ‘roughly correct’. In addition, I do not agree that ‘all the aggressive classes of T cells’ (CTL, for example) can be generated ‘near birth’. In any case I make the following comments. (a) I did postulate in the paper a role for regulatory T cells in the expression of the autoreactive B cell function; I did not address CTLs, but as such cells are systematically activated along with graft rejection and the fact that regulatory T cells impose graft tolerance, I would think that these do also
c
2000 Academic Press 1044–5323 / 00 / 030319+ 02 / $35.00 / 0
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Coutinho: round 3
tulate that regulatory T cells recognize antigens that are common to all B cells and therefore I do not see where there is the problem with ‘generalized suppression’ of B cells responses to nonself antigens.
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