Teaching the immune system ''self'' respect and tolerance Lucienne Chatenoud Science 344, 1343 (2014); DOI: 10.1126/science.1256864
This copy is for your personal, non-commercial use only.
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of June 19, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/344/6190/1343.full.html This article cites 15 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/344/6190/1343.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on June 20, 2014
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
in vitro expansion of substantial numbers of antigen-specific Treg cells is a challenge. An alternative approach is to promote the differentiation and expansion of autoantigen-specific Treg cells in vivo, without compromising other immune system functions. Massive production of the immunoregulatory cytokine transforming growth factor–β (TGF-β) by phagocytic cells, blocks the vicious cycle of self-perpetuating inflamBy Lucienne Chatenoud in tissues that become inflammatory tarmation that is the hallmark of all autoimgets. Recently, the central role of regulatory mune responses (10). This burst of TGF-β he immune system protects the indiT cells (Tregs) (4–7) in maintaining imoccurs when phagocytes engulf cells that vidual from infectious agents and the mune tolerance has spurred cell therapy are dying by programmed cell death (apopemergence of tumors while preservstrategies in which Tregs are isolated from tosis). In a host suffering from autoimmuing the host’s integrity (1). The latter an autoimmune patient, expanded in vitro, nity, a key question is how apoptosis of a implies that the immune system will and then reinjected into the individual (8, sufficient number of cells can be induced in not attack the individual’s own tissues 9). However, such studies use polyclonal vivo to stimulate the release of TGF-β from (“self”). This peaceful coexistence, or imTregs that are not antigen specific, and the phagocytes, all in the context of an immune mune tolerance, is broken when environment that supports the an autoimmune disease develgeneration of Treg cells to reEfector Self-antigen Antigenops, such as multiple sclerosis store self-tolerance? T cell presenting or insulin-dependent diabetes. Kasagi et al. demonstrate cell Tolerance is what we would like how this can be accomplished to restore to cure such disabling in two mouse models: induced diseases. Kasagi et al. (2) indicate experimental autoimmune enthat it may be possible to teach cephalitis (a model of multiple Infammatory response Autoimmune disease the immune system to tolerate sclerosis) and spontaneous “self” again. insulin-dependent diabetes in The pathogenesis of several nonobese diabetic (NOD) mice. Antibody Apoptosis treatment diseases involves a primary or The authors first established secondary autoimmune reacthat phagocytes are essention, and their incidence now tial to the approach. After constitutes the third leading destroying 60 to 80% of the TGF-β Immune cells cause of morbidity and mortality animal’s immune cells (inrelease (T and B) after cardiovascular disease and cluding phagocytes) by whole Phagocyte Autoimmune disease cancer (3). There is yet no cure body γ irradiation, the mouse for autoimmune diseases. For was replenished with normal those causing serious disabling phagocytes and was also inSelf-antigen Regulatory organ damage such as multiple jected with the antigen that treatment T cell sclerosis, lupus erythematosus, elicited the autoimmune reor rheumatoid arthritis, the sponse (autoantigen) in the first usual recourse is chronic treatplace. Remarkably, the autoimment with immunosuppressive mune disease was abolished drugs that globally depress the (see the figure). The authors Naïve T cell Autoimmune disease immune system. This can render (New immunoregulatory milieu) demonstrate that phagocytes, patients vulnerable to infections their production of TGF-β, and and tumors. the generation of Treg cells speRegulatory AntigenImmune tolerance is not incific for the autoantigen are all T cell presenting nate. It is established during necessary components of the cell fetal and postnatal development therapeutic approach. and relies on mechanisms that Moreover, Kasagi et al. could operate in lymphoid organs replace the whole-body radiawhere lymphocytes differentition protocol with the adminate (i.e., bone marrow and thyistration of two monoclonal Efector mus) as well as in peripheral antibodies directed to B cells T cell secondary lymphoid organs (to the CD20 B cell antigen) Suppression of (i.e., spleen, lymph nodes, inand T cells (to the CD8 T cell autoimmune disease Tolerance to self-antigen testinal lymphoid tissue) and antigen). Antibody-bound imBreakdown and reprogram. Immune tolerance is achieved an animal models of autoimmune mune cells were destroyed by disease in a two-step approach. Immune cell apoptosis is induced by administering antibodies apoptosis in the animal. Thus, Université Paris Descartes, Sorbonne Paris Cité, F-75475 Paris, France, and INSERM that recognize immune cells. This is followed by treatment with the specific autoantigen, by removing these two “innoU1151, Hôpital Necker-Enfants Malades, which stimulates the production of specific regulatory T cells. These cells suppress effector cent bystander” subsets of im75015 Paris, France. E-mail: lucienne. T cells (that also respond to the autoantigen) and therefore promote tolerance. mune cells, phagocytes were [email protected]
IMMUNOLOGY
Teaching the immune system “self” respect and tolerance
An anti-inflammatory milieu promotes immune tolerance
ILLUSTRATION: C. BICKEL/SCIENCE
T
SCIENCE sciencemag.org
20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
1343
INSIGHTS | P E R S P E C T I V E S
spared. This preserved the essential TGF-β burst and the generation of an environment in vivo conducive to the development of autoantigen-specific Treg cells (in response to injection with autoantigen). This “reprogrammed” immune system could still respond to bacterial antigen, so overall immunity in the animal appears not to have been compromised. What is the true origin of the autoantigenspecific Treg cells that are responsible for the therapeutic effect? It is not known whether they derive from the distinct lineage of CD4 T cells from the thymus (FoxP3+Treg cells) (4–6, 11). Alternatively, they may derive from conventional peripheral CD4 T cells under the influence of TGF-β and the autoantigen (12). It is also not clear whether autoantigen-specific Treg cells can be sustained over time at sufficient amounts to ensure that the needed balance between “effectors” and “regulators” underlying immune tolerance is maintained. From a more practical point of view, therapeutic autoantigens for major autoimmune diseases (such as multiple sclerosis and autoimmune insulin–dependent diabetes) are available as therapeutic products and are safe (13). Also, monoclonal antibodies that recognize CD20 are likewise available and are safe (14, 15); CD8 monoclonal antibodies are still in development after many years. Aside from the scientific questions that must be addressed, there is the question of forging a strong academic-industry relationship if we want the strategy described by Kasagi et al. to become a clinical reality. It may be that the approach has implications far beyond autoimmune diseases, extending to the arenas of tolerance induction in transplantation, gene therapy, and regenerative medicine. ■ REFERENCES
1. R. H. Schwartz, Cold Spring Harb. Perspect. Biol. 4, a006908 (2012). 2. S. Kasagi et al., Sci. Transl. Med. 6, 241ra78 (2014). 3. J. F. Bach, N. Engl. J. Med. 347, 911 (2002). 4. J. D. Fontenot, M. A. Gavin, A. Y. Rudensky, Nat. Immunol. 4, 330 (2003). 5. J. D. Fontenot et al., Immunity 22, 329 (2005). 6. S. Sakaguchi et al., Immunol. Rev. 212, 8 (2006). 7. S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, M. Toda, J. Immunol. 155, 1151 (1995). 8. N. Marek-Trzonkowska, M. Myśliwec, J. Siebert, P. Trzonkowski, Pediatr. Diabetes 14, 322 (2013). 9. Q. Tang, J. A. Bluestone, Cold Spring Harb. Perspect. Med.3, a015552 (2013). 10. S. Perruche et al., Nat. Med. 14, 528 (2008). 11. J. A. Bluestone, A. K. Abbas, Nat. Rev. Immunol. 3, 253 (2003). 12. W. Chen et al., J. Exp. Med. 198, 1875 (2003). 13. J. Ludvigsson et al., N. Engl. J. Med. 359, 1909 (2008). 14. S. L. Hauser et al., N. Engl. J. Med. 358, 676 (2008). 15. M. D. Pescovitz et al., N. Engl. J. Med. 361, 2143 (2009).
10.1126/science.1256864
1344
PHYSICS
Electronically erased Erasing knowledge of a quantum system changes its state By D. E. Feldman
T
he fate of Schrödinger’s cat depends on the particular path of a single electron. If the electron hits the trigger, which opens a bottle of poisonous gas, then the cat dies. If the path misses the trigger, the cat lives. According to quantum mechanics, electrons do not normally follow a definite trajectory. Instead, an electron can trace both paths at the same time. As a result, Schrödinger’s cat is both dead and alive. Quantum mechanics also teaches us that a “which-path” detector—that is, any measurement device that can show where the electron travels—forces the electron to choose just one path, thus sealing the cat’s destiny. But what will happen after the information collected by the
A
Arm 1 D1 System D2
S1
when confined to two dimensions in a very pure semiconductor in a strong magnetic field. This is known as the quantum Hall effect. In particular, transport is one-dimensional, with electrons following just a small set of paths determined by metallic gates on top of the sample. This property was used by Weisz et al. to define the allowed trajectories for electrons in the experiment (see the figure, panel A). The experimental setup consists of two identical devices, known as electronic MachZehnder interferometers (3). One of them plays the role of a quantum system under investigation; the other is a detector (see the figure, panel A). To understand the experiment, we first need to address how a single interferometer works. Electrons depart from terminal S1 along the upper and lower arms
B Eraser on
Arm 2 +
S3
Arm 3 Detector
D3
Eraser of
D4 Arm 4 Electronic quantum eraser. (A) A schematic of the device. Electrons follow arms 1 to 4 in the directions of the arrows. Electrons in arm 2 repel electrons in arm 3. (B) The eraser effect on the quantum interference of matter waves.
detector has been erased? The results of a semiconductor version of such an experiment, reported by Weisz et al. on page 1363 of this issue (1), suggest that the cat will come back to the middle ground between life and death. In contrast to classical physics, any measurement on a quantum system affects its behavior. Hence, the properties of the system depend on what questions one asks. For example, according to the uncertainty principle, it is meaningful to ask about a position or velocity of a quantum particle, but it cannot have a definite position and velocity at the same time. Weisz et al. add another twist: What happens if a question is asked but the answer (that is, the measurement result) is erased? To address this problem, Weisz et al. have realized an electronic quantum eraser in a semiconductor nanostructure as proposed by Kang (2). Electrons exhibit rich behavior
1 and 2 and are detected in terminals D1 and D2. If electrons were classical particles, the number of arrivals to D2 would simply be determined by the incoming current at S1. The wave-particle duality of quantum mechanics implies more complexity: Electrons propagate along paths 1 and 2 in the form of waves. The waves interfere where the two arms meet (essentially, the oscillations in the two waves add up). Hence, the output signal at D2 depends on the phase difference between the waves. The latter is controlled by the area between the device arms. Thus, the number of electron arrivals to D2 oscillates as a function of the area. In the two-interferometer system, electric forces result in repulsion between the electrons in the lower arm of the quantum system and those in the upper arm of the deDepartment of Physics, Brown University, Providence, RI 02912, USA. E-mail: [email protected]
sciencemag.org SCIENCE
20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
This copy is for your personal, non-commercial use only.
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of June 19, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/344/6190/1343.full.html This article cites 15 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/344/6190/1343.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on June 20, 2014
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
in vitro expansion of substantial numbers of antigen-specific Treg cells is a challenge. An alternative approach is to promote the differentiation and expansion of autoantigen-specific Treg cells in vivo, without compromising other immune system functions. Massive production of the immunoregulatory cytokine transforming growth factor–β (TGF-β) by phagocytic cells, blocks the vicious cycle of self-perpetuating inflamBy Lucienne Chatenoud in tissues that become inflammatory tarmation that is the hallmark of all autoimgets. Recently, the central role of regulatory mune responses (10). This burst of TGF-β he immune system protects the indiT cells (Tregs) (4–7) in maintaining imoccurs when phagocytes engulf cells that vidual from infectious agents and the mune tolerance has spurred cell therapy are dying by programmed cell death (apopemergence of tumors while preservstrategies in which Tregs are isolated from tosis). In a host suffering from autoimmuing the host’s integrity (1). The latter an autoimmune patient, expanded in vitro, nity, a key question is how apoptosis of a implies that the immune system will and then reinjected into the individual (8, sufficient number of cells can be induced in not attack the individual’s own tissues 9). However, such studies use polyclonal vivo to stimulate the release of TGF-β from (“self”). This peaceful coexistence, or imTregs that are not antigen specific, and the phagocytes, all in the context of an immune mune tolerance, is broken when environment that supports the an autoimmune disease develgeneration of Treg cells to reEfector Self-antigen Antigenops, such as multiple sclerosis store self-tolerance? T cell presenting or insulin-dependent diabetes. Kasagi et al. demonstrate cell Tolerance is what we would like how this can be accomplished to restore to cure such disabling in two mouse models: induced diseases. Kasagi et al. (2) indicate experimental autoimmune enthat it may be possible to teach cephalitis (a model of multiple Infammatory response Autoimmune disease the immune system to tolerate sclerosis) and spontaneous “self” again. insulin-dependent diabetes in The pathogenesis of several nonobese diabetic (NOD) mice. Antibody Apoptosis treatment diseases involves a primary or The authors first established secondary autoimmune reacthat phagocytes are essention, and their incidence now tial to the approach. After constitutes the third leading destroying 60 to 80% of the TGF-β Immune cells cause of morbidity and mortality animal’s immune cells (inrelease (T and B) after cardiovascular disease and cluding phagocytes) by whole Phagocyte Autoimmune disease cancer (3). There is yet no cure body γ irradiation, the mouse for autoimmune diseases. For was replenished with normal those causing serious disabling phagocytes and was also inSelf-antigen Regulatory organ damage such as multiple jected with the antigen that treatment T cell sclerosis, lupus erythematosus, elicited the autoimmune reor rheumatoid arthritis, the sponse (autoantigen) in the first usual recourse is chronic treatplace. Remarkably, the autoimment with immunosuppressive mune disease was abolished drugs that globally depress the (see the figure). The authors Naïve T cell Autoimmune disease immune system. This can render (New immunoregulatory milieu) demonstrate that phagocytes, patients vulnerable to infections their production of TGF-β, and and tumors. the generation of Treg cells speRegulatory AntigenImmune tolerance is not incific for the autoantigen are all T cell presenting nate. It is established during necessary components of the cell fetal and postnatal development therapeutic approach. and relies on mechanisms that Moreover, Kasagi et al. could operate in lymphoid organs replace the whole-body radiawhere lymphocytes differentition protocol with the adminate (i.e., bone marrow and thyistration of two monoclonal Efector mus) as well as in peripheral antibodies directed to B cells T cell secondary lymphoid organs (to the CD20 B cell antigen) Suppression of (i.e., spleen, lymph nodes, inand T cells (to the CD8 T cell autoimmune disease Tolerance to self-antigen testinal lymphoid tissue) and antigen). Antibody-bound imBreakdown and reprogram. Immune tolerance is achieved an animal models of autoimmune mune cells were destroyed by disease in a two-step approach. Immune cell apoptosis is induced by administering antibodies apoptosis in the animal. Thus, Université Paris Descartes, Sorbonne Paris Cité, F-75475 Paris, France, and INSERM that recognize immune cells. This is followed by treatment with the specific autoantigen, by removing these two “innoU1151, Hôpital Necker-Enfants Malades, which stimulates the production of specific regulatory T cells. These cells suppress effector cent bystander” subsets of im75015 Paris, France. E-mail: lucienne. T cells (that also respond to the autoantigen) and therefore promote tolerance. mune cells, phagocytes were [email protected]
IMMUNOLOGY
Teaching the immune system “self” respect and tolerance
An anti-inflammatory milieu promotes immune tolerance
ILLUSTRATION: C. BICKEL/SCIENCE
T
SCIENCE sciencemag.org
20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
1343
INSIGHTS | P E R S P E C T I V E S
spared. This preserved the essential TGF-β burst and the generation of an environment in vivo conducive to the development of autoantigen-specific Treg cells (in response to injection with autoantigen). This “reprogrammed” immune system could still respond to bacterial antigen, so overall immunity in the animal appears not to have been compromised. What is the true origin of the autoantigenspecific Treg cells that are responsible for the therapeutic effect? It is not known whether they derive from the distinct lineage of CD4 T cells from the thymus (FoxP3+Treg cells) (4–6, 11). Alternatively, they may derive from conventional peripheral CD4 T cells under the influence of TGF-β and the autoantigen (12). It is also not clear whether autoantigen-specific Treg cells can be sustained over time at sufficient amounts to ensure that the needed balance between “effectors” and “regulators” underlying immune tolerance is maintained. From a more practical point of view, therapeutic autoantigens for major autoimmune diseases (such as multiple sclerosis and autoimmune insulin–dependent diabetes) are available as therapeutic products and are safe (13). Also, monoclonal antibodies that recognize CD20 are likewise available and are safe (14, 15); CD8 monoclonal antibodies are still in development after many years. Aside from the scientific questions that must be addressed, there is the question of forging a strong academic-industry relationship if we want the strategy described by Kasagi et al. to become a clinical reality. It may be that the approach has implications far beyond autoimmune diseases, extending to the arenas of tolerance induction in transplantation, gene therapy, and regenerative medicine. ■ REFERENCES
1. R. H. Schwartz, Cold Spring Harb. Perspect. Biol. 4, a006908 (2012). 2. S. Kasagi et al., Sci. Transl. Med. 6, 241ra78 (2014). 3. J. F. Bach, N. Engl. J. Med. 347, 911 (2002). 4. J. D. Fontenot, M. A. Gavin, A. Y. Rudensky, Nat. Immunol. 4, 330 (2003). 5. J. D. Fontenot et al., Immunity 22, 329 (2005). 6. S. Sakaguchi et al., Immunol. Rev. 212, 8 (2006). 7. S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, M. Toda, J. Immunol. 155, 1151 (1995). 8. N. Marek-Trzonkowska, M. Myśliwec, J. Siebert, P. Trzonkowski, Pediatr. Diabetes 14, 322 (2013). 9. Q. Tang, J. A. Bluestone, Cold Spring Harb. Perspect. Med.3, a015552 (2013). 10. S. Perruche et al., Nat. Med. 14, 528 (2008). 11. J. A. Bluestone, A. K. Abbas, Nat. Rev. Immunol. 3, 253 (2003). 12. W. Chen et al., J. Exp. Med. 198, 1875 (2003). 13. J. Ludvigsson et al., N. Engl. J. Med. 359, 1909 (2008). 14. S. L. Hauser et al., N. Engl. J. Med. 358, 676 (2008). 15. M. D. Pescovitz et al., N. Engl. J. Med. 361, 2143 (2009).
10.1126/science.1256864
1344
PHYSICS
Electronically erased Erasing knowledge of a quantum system changes its state By D. E. Feldman
T
he fate of Schrödinger’s cat depends on the particular path of a single electron. If the electron hits the trigger, which opens a bottle of poisonous gas, then the cat dies. If the path misses the trigger, the cat lives. According to quantum mechanics, electrons do not normally follow a definite trajectory. Instead, an electron can trace both paths at the same time. As a result, Schrödinger’s cat is both dead and alive. Quantum mechanics also teaches us that a “which-path” detector—that is, any measurement device that can show where the electron travels—forces the electron to choose just one path, thus sealing the cat’s destiny. But what will happen after the information collected by the
A
Arm 1 D1 System D2
S1
when confined to two dimensions in a very pure semiconductor in a strong magnetic field. This is known as the quantum Hall effect. In particular, transport is one-dimensional, with electrons following just a small set of paths determined by metallic gates on top of the sample. This property was used by Weisz et al. to define the allowed trajectories for electrons in the experiment (see the figure, panel A). The experimental setup consists of two identical devices, known as electronic MachZehnder interferometers (3). One of them plays the role of a quantum system under investigation; the other is a detector (see the figure, panel A). To understand the experiment, we first need to address how a single interferometer works. Electrons depart from terminal S1 along the upper and lower arms
B Eraser on
Arm 2 +
S3
Arm 3 Detector
D3
Eraser of
D4 Arm 4 Electronic quantum eraser. (A) A schematic of the device. Electrons follow arms 1 to 4 in the directions of the arrows. Electrons in arm 2 repel electrons in arm 3. (B) The eraser effect on the quantum interference of matter waves.
detector has been erased? The results of a semiconductor version of such an experiment, reported by Weisz et al. on page 1363 of this issue (1), suggest that the cat will come back to the middle ground between life and death. In contrast to classical physics, any measurement on a quantum system affects its behavior. Hence, the properties of the system depend on what questions one asks. For example, according to the uncertainty principle, it is meaningful to ask about a position or velocity of a quantum particle, but it cannot have a definite position and velocity at the same time. Weisz et al. add another twist: What happens if a question is asked but the answer (that is, the measurement result) is erased? To address this problem, Weisz et al. have realized an electronic quantum eraser in a semiconductor nanostructure as proposed by Kang (2). Electrons exhibit rich behavior
1 and 2 and are detected in terminals D1 and D2. If electrons were classical particles, the number of arrivals to D2 would simply be determined by the incoming current at S1. The wave-particle duality of quantum mechanics implies more complexity: Electrons propagate along paths 1 and 2 in the form of waves. The waves interfere where the two arms meet (essentially, the oscillations in the two waves add up). Hence, the output signal at D2 depends on the phase difference between the waves. The latter is controlled by the area between the device arms. Thus, the number of electron arrivals to D2 oscillates as a function of the area. In the two-interferometer system, electric forces result in repulsion between the electrons in the lower arm of the quantum system and those in the upper arm of the deDepartment of Physics, Brown University, Providence, RI 02912, USA. E-mail: [email protected]
sciencemag.org SCIENCE
20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
