Immunology Today, vol. 8, Nos 7 andS, 1987
-lellers T cellsrecognizeantigen alone and not MHC molecules Sir, In a recePt article O. Werdelin (ImToday, 1987, 8, 80-84) argued that T cells might recognize antigen alone and not class II MHC molecules. We have previously defended a similar point of view 1 and incorporated the notion of 'MHCrestricted peptide presentation' into the framework of the 'peptidic self moder 2.3 of the immune system. This model has several key features. (1) Both class I and class II MHC gene products, members of the immunoglobulin superfamUy, are seen as peptide ~eceptors of loose specificities. (2) AUelic variations in MHC dass I or class II molecules usually result in the presentation of different peptides from the same antigen. (3) Self proteins are presented as peptides by self-MHC class I and class II molecules. (4) The immune system of an individual is tolerized against the particular (self-MHC restricted) set of peptides (somatic self) derived from its own proteins. It is only within this framework that we feel it possible to challenge the dogma of MHCrestricted antigen recognition by T cells and still be able to account for self/non-self discrimination. However; it must be noted that if the recognition of the polymorphic regions (private determinants) of MHC molecules by the T-cell receptor for antigen (TCR) is indeed dispensable, the correlation between T-cell function and the class of the restricting element (T helper cell/ class II, cytotoxic T cell/class I) requires at least some kind of MHC class discrimination. This might be achieved by accessory molecules (CD4, CD8. . . . . CDx) as proposed by others4. Less than optimal interaction between effector accessory molecules and public determinants on surface MHC antigens across species may account for the lesser intensity of xenogenic responses compared with allogenic responses. We wish to emphasize here that, in contrast with Werdelin, we do not think it necessary to discard the resuits obtained with lymphohemopoietic chimeras. Most of them are consistent with the 'priming hypothesis" (reviewed in Ref. 5) i.e. the selection of an MHC-specific determunol.
202
minant upon immunization. Only one type of experiment, as done by Sprent6. seems to argue strongly in favour of the 'ontogeny hypothesis', i.e. that T cells are irreversibly biased towards the recognition of self-MHC molecules during their maturation before encountering antigen. In this study, mice of parental strain P1 were reconstituted with F1 (P1 xP2) bone marrow. One year later, T cells from these chimeras were primed with antigen (SRBC)in another lethally irradiated F1 mouse, then assayed for in-vivo collaboration with P1 or P2 B cells in a third irradiated F1 mouse. Plaque-forming cells were only seen in the spleen of T + B(P1) reconstituted mice, thus apparently indicating that 'naive' T (F1 --, P1) cells could remember their education in a P1 thymus. In the framework of the 'self peptidic model' our alternative interpretation is as follows: F1 T cells (in particular cytotoxic cells) which develop in a P1 mouse are tolerized against self peptides as presented by MHC (P1) (but) not P2) class I molecules. Transfer of these cells into F1 irradiated mice results in an allogeneic boost (against self peptides presented by MHC (P2) molecules) and the subsequent killing of P2 B cells. The paradoxical finding that the restricted helper function is controlled, in this system, by the K-end of the H-2
* This letter was shown to Dr Werdelin, who replies as follows:
Sir, The reinterpretation of Sprent's experiment proposed by Claverie et el. is ingenious and full of appeal. I share with them a fondness for the idea that cells leaving the thymus have been made tolerant to those antigens which have been appropriately presented to them in the thymus, and that the population leaving for the periphery is responsive to antigens which have not been so presented. Their proposal raises new questions. Why would the antiP2 CTL kill only B lymphocytes and spare T lymphocytes? Why does the F1 hybrid harbouring such CTL not suffer from a full-scale graft-versushost reaction? I wish to emphasize that I do not discard the results obtained with lymphohemopoietic chimeras.
complex 7 does suggest the involvement of cytotoxic T cells. A similar argument can be made for the immuno-incompetence of fully allogenic (P1--~P2) chimeras (reviewed in Ref. 5). Thus, an observation thought to favor MHC-restricted recognition of antigen by helper T cells can be interpreted differently and appears compatible with the hypothesis of MHC-restricted peptide presentation in the framework of the 'peptidic self' model.
Jean-Michel Claverie G~rard Chaouat Chantal Rabourdin-Combe Philippe Kourilsky Institut Pasteur, 75724 Paris,France
References 1 Claverie,J.M. and Kourilsky, P. (1986) Ann. Inst. Pasteur lmmunol. 137 D,
425-442 2 Kourilsky,P. and Claverie, J.M. (1986) Ann. Inst. Pasteur lmmunol. 137 D, 3-21 3 Kourilsky,P., Chaouat, G., RabourdinCombe, C. and ClaverieJ.M. (1987)Proc. H~tl Acad. Sci. USA 84, 3400-3404 4 Goverrnan,J., Hunkapiller,T. and Hood, L. (1986) Cell45, 475-484 5 Schwartz,R.H.(1984)in Fundamental Immunology (Paul,W.E., ed.), pp. 379-438, RavenPress 6 Sprent,J. (1978) Immunol. Rev. 42, 108-137 7 Sprent,J. (1978)J. Exp. Mad. 147, 1838-1842
Rather, I reinterpret them and reach a conclusion with respect to MHC restriction which differs from the conventional one. The conventional view, which to a large extent is based upon the chimera experiments, is that T lymphocytes acquire their MHC restriction during the maturation in the thymus. This is based upon two complementary observations, namely that T lymphocytes primed in an F1 (bin)--~ P1 (irrad) chimera are predominantly restricted to the MHC of P1, whereas the population of T lymphocytes primed in a P1 ( b m ) - + F1 (irrad) chimera contain some members which are restricted to P1 MHC and others which are restricted to P2 MHC. I believe that the conventional view is wrong, because the chimera workers have made an assumption which is wrong. The wrong assumption is that the entire population of antigen-presenting cells in the
~:) 1987. ElsevierPublications,Cambridge 0~67-4919/87/$02.00
ImmunologyToday,vol. 8, Nos 7 and 8, 1987
peripheral tissues of the chimera is substituted with cells derived from the donor bone marrow. In some studies the investigators have checked lymph nodes and spleen for cells carrying the surface markers of the recipient type, and have found few or none at all after a couple of months. In other tissues, however, the chimera contains cells with antigen-presenting capacity, such as endothelial cells, which are not bone marrow-derived. Thus the chimera's antigen-presenting cells
Cytokinesin autoimmunity Sir, We wish to endorse the proposal by A. Cooke et al. (Immunol. Today, 1986, 7, 325) and J-J. Remy et al. (Immunol. Today, 1987, 8, 73)that tumor necrosis factor (TNF) and !nterferon (IFN) -~/may be important in the pathogenesis of autoimmune thyroid diseases. In addition, we suggest that the most important cytokine in this regard is interleukin 1 (IL-1). Bottazzo et al. 1 have demonstrated aberrant expression of class II (HLA-DR) molecules on thyroid cell membranes in autoimmune thyroid disorders. Class II molecules may facilitate presentation of thyroid antigens to autoreactive T cells and thus contribute to thyroid ceil dysfunction as a result of a T-cellmediated attack. However, expression of class II molecules depends on the presence not only of T lymphocytes but also of monocytes/ macrophages (MO) (Ref. 2). The reason for this is not clear, but it may be due to the fact that MO and MO-derived IL-1 are necessary for the activation of T cells to elaborate cytokines such as IFN--y (Ref. 3). In any case, MO appear to play a central role in these diseases, as indeed they do in other organ-specific autoimmune disorders, notably insulindependent diabetes mellitus (IDDM) (Ref. 4), where natural killer (NK) cells may be involved as well 5. IL-1 is produced primarily by activated MO but also by NK cellse.7, and IFN--y enhances the elaboration of !L-1 by these cells3. IL-1 is necessary for the induction of activated T lymphocytes, and IL-1 is almost certainly produced by MO and/or NK cells infiltrating the thyroid gland during autoimmune diseases. The predomi-
/e!/ers-are a mixture of don3r and recipient cells. Depending on the nature of the antigen and the mode of its administration the parental or the F1 population, or both, may be used as antigen-presenting cells during the priming phase of the immune response. This opens a new interpretation of the results of many of the chimera experiments, namely that the MHC restriction of the chimera's T lymphocytes is determined in the periphery at the time of their first meeting with the antigen. The MHC
of the cell which presents the antigen will become the restricting element. Thus most of the T lymphocytes primed in an F1 ( b i n ) ~ P1 (irrad) become restricted to the P1 MHC, not because they differentiated in the Pl thymus, but because they met the antigen on a P1 antigen-presenting cell.
nant species of human IL-1, termed IL-113, has been shown to be a potent suppressor of insulin production in vitro, most likely as a result of a direct and selective cytotoxic effect on pancreatic 13-cells8.9. We have therefore tested the effect in vitro of human recombinant IL-113 (rlL-113) on human paraadenomatous thyroid cells stimulated by 100 mU/I of thyroidstimulating hormone (TSH). At very low concentrations of rlL-113 (10-16-10-14M = 0.0001-O.001 U/ml; mouse thymocyte costimulator assay), the TSH-stimulated secretion of cAMP and thyroglobulin (TG) was enhanced (up to 190% compared with cells in TSH alone) Higher concentrations (10-12-10 -9M ---0.1-100 U/ml) dose-dependently suppressed TG and cAMP (down to 23% of controls). Similar responses have been obtained with regard to the effect of rlL-113 on insulin production by glucose-stimulated rat pancreatic 13-cells8.1°. Human recombinant TNF and IFN--ydid not by themselves or in combination affect the function of TSH-stimulated thyroid cells, but the rlL-113-induced inhibition of TG was augmented 30% (range 20-43%; n-12) by either rTNF ( 1 0 - 9 M = 1000 U/ml) or by rlFN--/ (2.5x10-1°M = 100 U/ ml). Electron micrographs showed that rlL-113 (2.5×10-.°M = 25 U/ml) completely prevented the ability of the TSH-activateo cells to form follicles and glycogen granules. Judged by these studies, the effect of II.-1 on thyroid cell function is inhibitory rather than cytotoxic, at least in short-term cultures. The findings indicate a central role of MO (and possibly NK cells) and their product II.-1 in autoimmune endocrine disease. TNF and IFN-~/
may play a significant role as well through their ability to induce and augment the production of IL-1, to potentiate the inhibitory effect of IL-1 on endocrine target cells, and by the ability of IFN-~/to induce class II molecules on thyroid cells and, in combination with TNF (Ref. 11), on human islet cells. In addition, IL-1 may fulfil an important physiological role in the regulation of the endocrine system. During conditions of 'stress' low concentrations of IL-1 may accumulate in endocrine tissues by diffusion from the blood; this would serve a beneficial function by potentiating TG and insulin production under these circumstances.
~) 1987, Elsevier Publications. Cambridge 0167 - 4919/87/$02.00
Ole Werdelin Institutefor ExperimentalImmunology, Universityof Copenhagen,DK-2100 Copenhagen0, Denmark
KlausBendtzen Laboratory,of Medical-!_.~_.u..no!__~=,, RigshospitaletUniversityHospital,DK-2200 CopenhagenN, Denmark
.,~ KroghRasmussen FrederiksbergHospital,Ndr. Fasanvej59, DK2200 CopenhagenIV,Denmark
KarineBeth Hvid~reDiabetesHospital,Emiliekildevej1, DK-2930Klampenborg,Denmark
Ulla Feldt.Rasmussen Gentofte UniversityHospital,N,els Andersensvej65, DK-2900Hellerup,Denmark
Jem Egeberg PanumInstitute, CopenhagenUniversity, 81egdamsvej3C, DK-2200CopenhagenN, Denmark
References
1 Bottazzo,G.F.,PujoI-Borrell,R., Hanafusa,T. etal. (1983)Lancet ii, 1115-1119 2 Iwatani,Y., Gerstein,H.C.,Itaka, M. et al. (1986)J. Clin. Endocrinol. Metab. 63, 659-708 3 Trinchieri,G. and Perussia,B. (1985)
203
-lellers T cellsrecognizeantigen alone and not MHC molecules Sir, In a recePt article O. Werdelin (ImToday, 1987, 8, 80-84) argued that T cells might recognize antigen alone and not class II MHC molecules. We have previously defended a similar point of view 1 and incorporated the notion of 'MHCrestricted peptide presentation' into the framework of the 'peptidic self moder 2.3 of the immune system. This model has several key features. (1) Both class I and class II MHC gene products, members of the immunoglobulin superfamUy, are seen as peptide ~eceptors of loose specificities. (2) AUelic variations in MHC dass I or class II molecules usually result in the presentation of different peptides from the same antigen. (3) Self proteins are presented as peptides by self-MHC class I and class II molecules. (4) The immune system of an individual is tolerized against the particular (self-MHC restricted) set of peptides (somatic self) derived from its own proteins. It is only within this framework that we feel it possible to challenge the dogma of MHCrestricted antigen recognition by T cells and still be able to account for self/non-self discrimination. However; it must be noted that if the recognition of the polymorphic regions (private determinants) of MHC molecules by the T-cell receptor for antigen (TCR) is indeed dispensable, the correlation between T-cell function and the class of the restricting element (T helper cell/ class II, cytotoxic T cell/class I) requires at least some kind of MHC class discrimination. This might be achieved by accessory molecules (CD4, CD8. . . . . CDx) as proposed by others4. Less than optimal interaction between effector accessory molecules and public determinants on surface MHC antigens across species may account for the lesser intensity of xenogenic responses compared with allogenic responses. We wish to emphasize here that, in contrast with Werdelin, we do not think it necessary to discard the resuits obtained with lymphohemopoietic chimeras. Most of them are consistent with the 'priming hypothesis" (reviewed in Ref. 5) i.e. the selection of an MHC-specific determunol.
202
minant upon immunization. Only one type of experiment, as done by Sprent6. seems to argue strongly in favour of the 'ontogeny hypothesis', i.e. that T cells are irreversibly biased towards the recognition of self-MHC molecules during their maturation before encountering antigen. In this study, mice of parental strain P1 were reconstituted with F1 (P1 xP2) bone marrow. One year later, T cells from these chimeras were primed with antigen (SRBC)in another lethally irradiated F1 mouse, then assayed for in-vivo collaboration with P1 or P2 B cells in a third irradiated F1 mouse. Plaque-forming cells were only seen in the spleen of T + B(P1) reconstituted mice, thus apparently indicating that 'naive' T (F1 --, P1) cells could remember their education in a P1 thymus. In the framework of the 'self peptidic model' our alternative interpretation is as follows: F1 T cells (in particular cytotoxic cells) which develop in a P1 mouse are tolerized against self peptides as presented by MHC (P1) (but) not P2) class I molecules. Transfer of these cells into F1 irradiated mice results in an allogeneic boost (against self peptides presented by MHC (P2) molecules) and the subsequent killing of P2 B cells. The paradoxical finding that the restricted helper function is controlled, in this system, by the K-end of the H-2
* This letter was shown to Dr Werdelin, who replies as follows:
Sir, The reinterpretation of Sprent's experiment proposed by Claverie et el. is ingenious and full of appeal. I share with them a fondness for the idea that cells leaving the thymus have been made tolerant to those antigens which have been appropriately presented to them in the thymus, and that the population leaving for the periphery is responsive to antigens which have not been so presented. Their proposal raises new questions. Why would the antiP2 CTL kill only B lymphocytes and spare T lymphocytes? Why does the F1 hybrid harbouring such CTL not suffer from a full-scale graft-versushost reaction? I wish to emphasize that I do not discard the results obtained with lymphohemopoietic chimeras.
complex 7 does suggest the involvement of cytotoxic T cells. A similar argument can be made for the immuno-incompetence of fully allogenic (P1--~P2) chimeras (reviewed in Ref. 5). Thus, an observation thought to favor MHC-restricted recognition of antigen by helper T cells can be interpreted differently and appears compatible with the hypothesis of MHC-restricted peptide presentation in the framework of the 'peptidic self' model.
Jean-Michel Claverie G~rard Chaouat Chantal Rabourdin-Combe Philippe Kourilsky Institut Pasteur, 75724 Paris,France
References 1 Claverie,J.M. and Kourilsky, P. (1986) Ann. Inst. Pasteur lmmunol. 137 D,
425-442 2 Kourilsky,P. and Claverie, J.M. (1986) Ann. Inst. Pasteur lmmunol. 137 D, 3-21 3 Kourilsky,P., Chaouat, G., RabourdinCombe, C. and ClaverieJ.M. (1987)Proc. H~tl Acad. Sci. USA 84, 3400-3404 4 Goverrnan,J., Hunkapiller,T. and Hood, L. (1986) Cell45, 475-484 5 Schwartz,R.H.(1984)in Fundamental Immunology (Paul,W.E., ed.), pp. 379-438, RavenPress 6 Sprent,J. (1978) Immunol. Rev. 42, 108-137 7 Sprent,J. (1978)J. Exp. Mad. 147, 1838-1842
Rather, I reinterpret them and reach a conclusion with respect to MHC restriction which differs from the conventional one. The conventional view, which to a large extent is based upon the chimera experiments, is that T lymphocytes acquire their MHC restriction during the maturation in the thymus. This is based upon two complementary observations, namely that T lymphocytes primed in an F1 (bin)--~ P1 (irrad) chimera are predominantly restricted to the MHC of P1, whereas the population of T lymphocytes primed in a P1 ( b m ) - + F1 (irrad) chimera contain some members which are restricted to P1 MHC and others which are restricted to P2 MHC. I believe that the conventional view is wrong, because the chimera workers have made an assumption which is wrong. The wrong assumption is that the entire population of antigen-presenting cells in the
~:) 1987. ElsevierPublications,Cambridge 0~67-4919/87/$02.00
ImmunologyToday,vol. 8, Nos 7 and 8, 1987
peripheral tissues of the chimera is substituted with cells derived from the donor bone marrow. In some studies the investigators have checked lymph nodes and spleen for cells carrying the surface markers of the recipient type, and have found few or none at all after a couple of months. In other tissues, however, the chimera contains cells with antigen-presenting capacity, such as endothelial cells, which are not bone marrow-derived. Thus the chimera's antigen-presenting cells
Cytokinesin autoimmunity Sir, We wish to endorse the proposal by A. Cooke et al. (Immunol. Today, 1986, 7, 325) and J-J. Remy et al. (Immunol. Today, 1987, 8, 73)that tumor necrosis factor (TNF) and !nterferon (IFN) -~/may be important in the pathogenesis of autoimmune thyroid diseases. In addition, we suggest that the most important cytokine in this regard is interleukin 1 (IL-1). Bottazzo et al. 1 have demonstrated aberrant expression of class II (HLA-DR) molecules on thyroid cell membranes in autoimmune thyroid disorders. Class II molecules may facilitate presentation of thyroid antigens to autoreactive T cells and thus contribute to thyroid ceil dysfunction as a result of a T-cellmediated attack. However, expression of class II molecules depends on the presence not only of T lymphocytes but also of monocytes/ macrophages (MO) (Ref. 2). The reason for this is not clear, but it may be due to the fact that MO and MO-derived IL-1 are necessary for the activation of T cells to elaborate cytokines such as IFN--y (Ref. 3). In any case, MO appear to play a central role in these diseases, as indeed they do in other organ-specific autoimmune disorders, notably insulindependent diabetes mellitus (IDDM) (Ref. 4), where natural killer (NK) cells may be involved as well 5. IL-1 is produced primarily by activated MO but also by NK cellse.7, and IFN--y enhances the elaboration of !L-1 by these cells3. IL-1 is necessary for the induction of activated T lymphocytes, and IL-1 is almost certainly produced by MO and/or NK cells infiltrating the thyroid gland during autoimmune diseases. The predomi-
/e!/ers-are a mixture of don3r and recipient cells. Depending on the nature of the antigen and the mode of its administration the parental or the F1 population, or both, may be used as antigen-presenting cells during the priming phase of the immune response. This opens a new interpretation of the results of many of the chimera experiments, namely that the MHC restriction of the chimera's T lymphocytes is determined in the periphery at the time of their first meeting with the antigen. The MHC
of the cell which presents the antigen will become the restricting element. Thus most of the T lymphocytes primed in an F1 ( b i n ) ~ P1 (irrad) become restricted to the P1 MHC, not because they differentiated in the Pl thymus, but because they met the antigen on a P1 antigen-presenting cell.
nant species of human IL-1, termed IL-113, has been shown to be a potent suppressor of insulin production in vitro, most likely as a result of a direct and selective cytotoxic effect on pancreatic 13-cells8.9. We have therefore tested the effect in vitro of human recombinant IL-113 (rlL-113) on human paraadenomatous thyroid cells stimulated by 100 mU/I of thyroidstimulating hormone (TSH). At very low concentrations of rlL-113 (10-16-10-14M = 0.0001-O.001 U/ml; mouse thymocyte costimulator assay), the TSH-stimulated secretion of cAMP and thyroglobulin (TG) was enhanced (up to 190% compared with cells in TSH alone) Higher concentrations (10-12-10 -9M ---0.1-100 U/ml) dose-dependently suppressed TG and cAMP (down to 23% of controls). Similar responses have been obtained with regard to the effect of rlL-113 on insulin production by glucose-stimulated rat pancreatic 13-cells8.1°. Human recombinant TNF and IFN--ydid not by themselves or in combination affect the function of TSH-stimulated thyroid cells, but the rlL-113-induced inhibition of TG was augmented 30% (range 20-43%; n-12) by either rTNF ( 1 0 - 9 M = 1000 U/ml) or by rlFN--/ (2.5x10-1°M = 100 U/ ml). Electron micrographs showed that rlL-113 (2.5×10-.°M = 25 U/ml) completely prevented the ability of the TSH-activateo cells to form follicles and glycogen granules. Judged by these studies, the effect of II.-1 on thyroid cell function is inhibitory rather than cytotoxic, at least in short-term cultures. The findings indicate a central role of MO (and possibly NK cells) and their product II.-1 in autoimmune endocrine disease. TNF and IFN-~/
may play a significant role as well through their ability to induce and augment the production of IL-1, to potentiate the inhibitory effect of IL-1 on endocrine target cells, and by the ability of IFN-~/to induce class II molecules on thyroid cells and, in combination with TNF (Ref. 11), on human islet cells. In addition, IL-1 may fulfil an important physiological role in the regulation of the endocrine system. During conditions of 'stress' low concentrations of IL-1 may accumulate in endocrine tissues by diffusion from the blood; this would serve a beneficial function by potentiating TG and insulin production under these circumstances.
~) 1987, Elsevier Publications. Cambridge 0167 - 4919/87/$02.00
Ole Werdelin Institutefor ExperimentalImmunology, Universityof Copenhagen,DK-2100 Copenhagen0, Denmark
KlausBendtzen Laboratory,of Medical-!_.~_.u..no!__~=,, RigshospitaletUniversityHospital,DK-2200 CopenhagenN, Denmark
.,~ KroghRasmussen FrederiksbergHospital,Ndr. Fasanvej59, DK2200 CopenhagenIV,Denmark
KarineBeth Hvid~reDiabetesHospital,Emiliekildevej1, DK-2930Klampenborg,Denmark
Ulla Feldt.Rasmussen Gentofte UniversityHospital,N,els Andersensvej65, DK-2900Hellerup,Denmark
Jem Egeberg PanumInstitute, CopenhagenUniversity, 81egdamsvej3C, DK-2200CopenhagenN, Denmark
References
1 Bottazzo,G.F.,PujoI-Borrell,R., Hanafusa,T. etal. (1983)Lancet ii, 1115-1119 2 Iwatani,Y., Gerstein,H.C.,Itaka, M. et al. (1986)J. Clin. Endocrinol. Metab. 63, 659-708 3 Trinchieri,G. and Perussia,B. (1985)
203
