- Email: [email protected]
tolerance decision
Medical Hypotheses (2005) 64, 112–113
http://intl.elsevierhealth.com/journals/mehy
Dendritic cells and the immunity/tolerance decision David Usharauli* Department of Immun ology, Institute of Medical Biotechnology, Chiaureli Str. #2, Tbilisi 0159 (formerly 380059), Georgia Received 26 March 2003; accepted 2 February 2004
Summary The role of dentritic cells in initiating the immune response has been well established. Recent studies point to an important role for DCs in the induction of peripheral tolerance as well. It was proposed that the role of DC in the immunity/tolerance decision could be associated simply with DC maturation states. However, it has been observed that immature DC do not process endocytosed antigens well to form MHC + peptide complexes and therefore selfspecific T cells would not be able to recognize their ligands on immature DCs. Then how might immature DCs induce tolerance to self-antigens? Below it is discussed a new mechanism which might control whether the DCs behavior will be tolerogenic or immunogenic. The hypothesis proposed that DCs should have two maturation programs operating in absence/presence of Danger signals leading to mature-tolerogenic and mature-immunogenic phenotypes, respectively. c 2004 Published by Elsevier Ltd.
Introduction Central or thymic tolerance is likely not capable of deleting T cells specific to self-antigens expressed on peripheral tissues [1]. Therefore, many self-specific T cells need to be silenced in the periphery to prevent immune responses to self [1,2]. DCs are present in almost all peripheral tissues [3]. While the role of DC in initiating immune responses has been well established [4], many are now pursuing their role in tolerance induction. The findings suggest that immature DCs continually endocytosed
*
Present address: Antonovskajas 9, #33, Tbilisi 0177 (formerly 380077), Georgia. E-mail address: [email protected].
0306-9877/$ - see front matter c 2004 Published by Elsevier Ltd. doi:10.1016/j.mehy.2004.02.061
apoptotic cells dying in peripheral tissues and transport them to T cells areas of local lymph nodes [3,5]. Accordingly, DCs may be able to present peripheral self-antigens to T cells and thus induce tolerance to self-antigens, which have no access to the thymus. These observations raised the question of what determines whether DCs turn the immune system on or off [6]? Two main hypotheses have been put forward to explain such a dichotomy in behavior of DCs. The first hypothesis argues that the role of DC in the immunity/tolerance decision could be associated with DC maturation states, i.e., immature DCs lacking co-stimulation may induce tolerance. However it has been correctly pointed out that immature DC do not process endocytosed antigens well to form MHC + peptide complexes on cell surface [2]. There-
Dendritic cells and the immunity/tolerance decision fore self-specific T cells would not be able to recognize their ligand on immature DCs. Moreover it was also shown that a maturation signal is necessary to induce migration of immature DCs from peripheral tissue to local lymph nodes [2]. How might then immature DCs induce tolerance to self-antigens? The second hypothesis proposed the presence of a separate tolerogenic DC lineage [7,8]. But such a tolerogenic DC lineage might provide an easy target for pathogens which could use tolerogenic DCs to induce tolerance to their own antigens, i.e., there would need to be a mechanism to prevent association of self with nonself antigens in tolerogenic DCs [10].
113 ed with models that postulate a primary role for DCs in the tolerance/immunity decision. In the end it would be relevant to point the possible experimental test to distinguish between these two maturation programs. It would be logical to assume that tolerogenic maturation of DC might induce up-regulation of molecules that are shown to be involved in T cell tolerance like FasL, IL-10 or TGF-beta. Use of DCs KO for those effector molecules in adoptive transfer experiments might shed the light on this issue.
Acknowledgements ‘‘Double-faced Janus’’ – a hypothesis The new hypothesis is proposed to overcome the difficulties mentioned above. It predicts that there should be at least two maturation programs of a single DC lineage that control immunogenic or tolerogenic phenotypes. In the absence of Danger signals immature DCs undergo maturation spontaneously, in a time-dependent manner, leading to a maturetolerogenic phenotype, i.e., all antigens captured before Danger-free maturation are considered as self by the immune system. In the presence of Danger signals DCs also undergo maturation but of a different kind. Danger signals activate an alternative maturation program leading to a mature-immunogenic phenotype [9]. Both maturation programs are terminal so no tolerogenic phenotype could be converted into immunogenic phenotype and vice versa. The next question to be answered was how to prevent association of Self with Nonself antigens in tolerogenic DCs. The new hypothesis gives a clue for it also. It suggests that maturation signals irrespective of their origin (time or Danger-dependent) induce expression of all MHC + epitope complexes on the surface of DCs in a single wave manner, i.e., expression of MHC + epitope complexes on surface of DCs is a single event and no new MHC + epitope complexes are formed after this first wave [11]. Such a mechanism prevents association of Self with Nonself antigens in tolerogenic DCs even in cases where a pathogen infects tolerogenic DCs because the pathogens will be not able to load their own epitopes into new MHC molecules. This new hypothesis outlines mechanisms that overcome the difficulties that have been associat-
I want to thank J.D. Gamrekelashvili and G. Lominadze for critically reviewing manuscript. Special thanks to Colin C. Anderson.
References [1] Kruisbeek AM, Amsen D. Mechanisms underlying T cell tolerance. Curr Opin Immunol 1996;8:233–44. [2] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52. [3] Steinman RM, Turley S, Mellman T, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000;191:411–6. [4] Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991;9:271–96. [5] Huang FG, Platt N, Wykes M, Major J, Powell T, Jenkins G et al. A discrete subpopulation of Dendritic cells transport apoptotic intestinal epithelial cells to T cell area of mesenteric lymph nodes. J Exp Med 2000;191: 435–43. [6] Finkelman FD, Lees A, Birnbaum R, Gause WC, Morris SC. Dendritic cells can present antigen in vivo in a tolerogenic or, immunogenic fashion. J Immunol 1996;157: 1406–14. [7] Maldonado-Lopez R, De Smedt T, Michel P, Godfroid J, Pajak B, Heirman C et al. CD8a+ and CD8a subclasses of dendritic cells direct the development of distinct Th cells in vivo. J Exp Med 1999;189:587–92. [8] Suss G, Shortman K. A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand induced apoptosis. J Exp Med 1996;183:1789–96. [9] Matzinger P. Tolerance, danger and the extended family. Annu Rev Immunol 1994;12:991–1045. [10] Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970;169:1042–9. [11] Landmann Salome ´, Mu ¨hlethaler-Mottet Annick, Bernasconi Tobias, Suter Tobias, Waldburger Jean-Marc, Masternak Krzysztof et al. Maturation of dendritic cells is accompanied by rapid transcriptional silencing of class II transactivator (CIITA) expression. J Exp Med 2001;194(Aug): 379–92.
http://intl.elsevierhealth.com/journals/mehy
Dendritic cells and the immunity/tolerance decision David Usharauli* Department of Immun ology, Institute of Medical Biotechnology, Chiaureli Str. #2, Tbilisi 0159 (formerly 380059), Georgia Received 26 March 2003; accepted 2 February 2004
Summary The role of dentritic cells in initiating the immune response has been well established. Recent studies point to an important role for DCs in the induction of peripheral tolerance as well. It was proposed that the role of DC in the immunity/tolerance decision could be associated simply with DC maturation states. However, it has been observed that immature DC do not process endocytosed antigens well to form MHC + peptide complexes and therefore selfspecific T cells would not be able to recognize their ligands on immature DCs. Then how might immature DCs induce tolerance to self-antigens? Below it is discussed a new mechanism which might control whether the DCs behavior will be tolerogenic or immunogenic. The hypothesis proposed that DCs should have two maturation programs operating in absence/presence of Danger signals leading to mature-tolerogenic and mature-immunogenic phenotypes, respectively. c 2004 Published by Elsevier Ltd.
Introduction Central or thymic tolerance is likely not capable of deleting T cells specific to self-antigens expressed on peripheral tissues [1]. Therefore, many self-specific T cells need to be silenced in the periphery to prevent immune responses to self [1,2]. DCs are present in almost all peripheral tissues [3]. While the role of DC in initiating immune responses has been well established [4], many are now pursuing their role in tolerance induction. The findings suggest that immature DCs continually endocytosed
*
Present address: Antonovskajas 9, #33, Tbilisi 0177 (formerly 380077), Georgia. E-mail address: [email protected].
0306-9877/$ - see front matter c 2004 Published by Elsevier Ltd. doi:10.1016/j.mehy.2004.02.061
apoptotic cells dying in peripheral tissues and transport them to T cells areas of local lymph nodes [3,5]. Accordingly, DCs may be able to present peripheral self-antigens to T cells and thus induce tolerance to self-antigens, which have no access to the thymus. These observations raised the question of what determines whether DCs turn the immune system on or off [6]? Two main hypotheses have been put forward to explain such a dichotomy in behavior of DCs. The first hypothesis argues that the role of DC in the immunity/tolerance decision could be associated with DC maturation states, i.e., immature DCs lacking co-stimulation may induce tolerance. However it has been correctly pointed out that immature DC do not process endocytosed antigens well to form MHC + peptide complexes on cell surface [2]. There-
Dendritic cells and the immunity/tolerance decision fore self-specific T cells would not be able to recognize their ligand on immature DCs. Moreover it was also shown that a maturation signal is necessary to induce migration of immature DCs from peripheral tissue to local lymph nodes [2]. How might then immature DCs induce tolerance to self-antigens? The second hypothesis proposed the presence of a separate tolerogenic DC lineage [7,8]. But such a tolerogenic DC lineage might provide an easy target for pathogens which could use tolerogenic DCs to induce tolerance to their own antigens, i.e., there would need to be a mechanism to prevent association of self with nonself antigens in tolerogenic DCs [10].
113 ed with models that postulate a primary role for DCs in the tolerance/immunity decision. In the end it would be relevant to point the possible experimental test to distinguish between these two maturation programs. It would be logical to assume that tolerogenic maturation of DC might induce up-regulation of molecules that are shown to be involved in T cell tolerance like FasL, IL-10 or TGF-beta. Use of DCs KO for those effector molecules in adoptive transfer experiments might shed the light on this issue.
Acknowledgements ‘‘Double-faced Janus’’ – a hypothesis The new hypothesis is proposed to overcome the difficulties mentioned above. It predicts that there should be at least two maturation programs of a single DC lineage that control immunogenic or tolerogenic phenotypes. In the absence of Danger signals immature DCs undergo maturation spontaneously, in a time-dependent manner, leading to a maturetolerogenic phenotype, i.e., all antigens captured before Danger-free maturation are considered as self by the immune system. In the presence of Danger signals DCs also undergo maturation but of a different kind. Danger signals activate an alternative maturation program leading to a mature-immunogenic phenotype [9]. Both maturation programs are terminal so no tolerogenic phenotype could be converted into immunogenic phenotype and vice versa. The next question to be answered was how to prevent association of Self with Nonself antigens in tolerogenic DCs. The new hypothesis gives a clue for it also. It suggests that maturation signals irrespective of their origin (time or Danger-dependent) induce expression of all MHC + epitope complexes on the surface of DCs in a single wave manner, i.e., expression of MHC + epitope complexes on surface of DCs is a single event and no new MHC + epitope complexes are formed after this first wave [11]. Such a mechanism prevents association of Self with Nonself antigens in tolerogenic DCs even in cases where a pathogen infects tolerogenic DCs because the pathogens will be not able to load their own epitopes into new MHC molecules. This new hypothesis outlines mechanisms that overcome the difficulties that have been associat-
I want to thank J.D. Gamrekelashvili and G. Lominadze for critically reviewing manuscript. Special thanks to Colin C. Anderson.
References [1] Kruisbeek AM, Amsen D. Mechanisms underlying T cell tolerance. Curr Opin Immunol 1996;8:233–44. [2] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52. [3] Steinman RM, Turley S, Mellman T, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000;191:411–6. [4] Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991;9:271–96. [5] Huang FG, Platt N, Wykes M, Major J, Powell T, Jenkins G et al. A discrete subpopulation of Dendritic cells transport apoptotic intestinal epithelial cells to T cell area of mesenteric lymph nodes. J Exp Med 2000;191: 435–43. [6] Finkelman FD, Lees A, Birnbaum R, Gause WC, Morris SC. Dendritic cells can present antigen in vivo in a tolerogenic or, immunogenic fashion. J Immunol 1996;157: 1406–14. [7] Maldonado-Lopez R, De Smedt T, Michel P, Godfroid J, Pajak B, Heirman C et al. CD8a+ and CD8a subclasses of dendritic cells direct the development of distinct Th cells in vivo. J Exp Med 1999;189:587–92. [8] Suss G, Shortman K. A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand induced apoptosis. J Exp Med 1996;183:1789–96. [9] Matzinger P. Tolerance, danger and the extended family. Annu Rev Immunol 1994;12:991–1045. [10] Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970;169:1042–9. [11] Landmann Salome ´, Mu ¨hlethaler-Mottet Annick, Bernasconi Tobias, Suter Tobias, Waldburger Jean-Marc, Masternak Krzysztof et al. Maturation of dendritic cells is accompanied by rapid transcriptional silencing of class II transactivator (CIITA) expression. J Exp Med 2001;194(Aug): 379–92.