NEWS & VIEWS RESEARCH lipids (glycolipids and phospholipids) with different chain lengths and degrees of unsaturation. They then used several strategies to detect antigenic activity in this melange, including tests of synthetic molecules that had the same molecular masses as the mater­ ial eluted from CD1a, and of partially purified lipids from various cell types. The authors found that epidermal lipids bound to CD1a were more stimulatory for the CD1a-reactive T cells than lipids from other cell types. More specifically, they showed that CD1a-reactive T cells recognized highly hydrophobic compounds such as squalene and triacyl­glyceride, which are found naturally in the skin, when these were bound to CD1a. This reactivity was selective, and other hydrophobic molecules such as cholesterol were not recognized by the cells. Although CD1 molecules have a hydro­ phobic antigen-binding groove, the completely hydrophobic character of the antigens presented by CD1a is surprising. T-cell antigen receptors typically recognize a composite structure of the antigen-presenting molecule and the antigen, with the exposed portion of the antigen participating in engaging the T-cell receptor (Fig. 1a). The exposed portion of lipid antigens is normally hydrophilic, containing a sugar or phosphate group, with the hydrophobic chains buried in the CD1 groove7. But the CD1a-binding self-reactive T cells did not obey this rule, because they did not require an exposed hydrophilic portion of the stimulatory lipid-containing antigen. In fact, binding of lipids bearing hydrophilic groups to CD1a inhibited the response of these T cells, presumably by competing with more strongly hydrophobic antigens for binding into the CD1a groove. Therefore, it seems that the self-reactive T-cell antigen receptor requires a view of CD1a that is unimpeded by exposed hydrophilic groups; the bound lipid may simply permit or stabilize CD1a into the correct conformation. As a consequence, rather than recognizing single compounds with high specificity, these T cells can be stimulated by a range of highly hydrophobic substances that fit in the CD1a groove. The skin forms a barrier to microbes through the generation of sebum — a highly hydrophobic substance synthesized in the sebaceous glands and secreted onto the outermost layer of the skin. Using micro­dissected sebaceous glands, de Jong et al. demonstrated that sebum is highly stimulatory for CD1a-dependent self-reactive T cells, and that it is rich in antigenic compounds, such as squalene. However, sebum is not typically in contact with the underlying dermal and epidermal layers that contain T cells and Langerhans cells. In normal skin, this physical separation may prevent CD1a-binding self-reactive T cells from being constantly exposed to their antigens. But disruption of the skin barrier by injury, infection or inflammation might allow sebum contents

to permeate the epidermis and bind to CD1aexpressing Langerhans cells, thereby stimulating T-cell responses (Fig. 1b). Although this may aid general immune defences, in cases of prolonged barrier disruption, constant exposure of immune cells to sebum could contribute to autoimmune skin diseases such as psoriasis and atopic dermatitis. Interestingly, squalene is currently used as an immune booster (adjuvant) to enhance the efficacy of vaccines and immunotherapies, and as a carrier for topical delivery to hair follicles of drugs for treating hair loss8. An auto­immune syndrome has also been described that is induced by adjuvants, including squalene9. It is possible that activation of CD1a-binding self-reactive T cells contributes to this compound’s immune-stimulating effects. Certainly, further investigation of the regulation of these T-cell responses to skin oils is warranted, both for understanding immunity and autoimmunity and in light of the

increasing therapeutic use of such agents. ■ Mitchell Kronenberg is at the La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA. Wendy L. Havran is at the Scripps Research Institute, La Jolla, California 92037, USA. e-mails: [email protected]; [email protected] 1. de Jong, A. et al. Nature Immunol. 15, 177–185 (2014). 2. Cheroutre, H., Lambolez, F. & Mucida, D. Nature Rev. Immunol. 11, 445–456 (2011). 3. Witherden, D. A. & Havran, W. L. J. Leuk. Biol. 94, 69–76 (2013). 4. Salio, M., Silk, J. D. & Cerundolo, V. Curr. Opin. Immunol. 22, 81–88 (2010). 5. de Jong, A. et al. Nature Immunol. 11, 1102–1109 (2010). 6. de Lalla, C. et al. Eur. J. Immunol. 41, 602–610 (2011). 7. Zajonc, D. M. & Kronenberg, M. Curr. Opin. Struct. Biol. 17, 521–529 (2007). 8. Aljuffali, I. A., Sung, C. T., Shen, F.-M., Huang, C.-T. & Fang, J.-Y. AAPS J. 16, 140–150 (2014). 9. Vera-Lastra, O., Medina, G., Cruz-Dominguez, M. Del P., Jara, L. J. & Shoenfeld, Y. Expert Rev. Clin. Immunol. 9, 361–373 (2013).

PA RTI C L E P H YS I CS

Quarks are not ambidextrous By separately scattering right- and left-handed electrons off quarks in a deuterium target, researchers have improved, by about a factor of five, on a classic result of mirror-symmetry breaking from 35 years ago. See Letter p.67 WILLIAM J. MARCIANO

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ymmetry makes the world go round. Scientific theories of the physics of elementary particles stem from simple symmetries that dictate the fundamental forces governing our Universe. Sometimes symmetries are broken, and that can have profound implications. An important case is the reflection, or right–left mirror, symmetry known as parity. On page 67 of this issue, an inter­national team at the Thomas Jefferson National Accelerator Facility in Newport News, Virginia, reports1 measurements of parity-symmetry breaking that confirm expectations and that unambiguously separate the electron and (much smaller) quark parityviolating inter­actions. The small quark parity violation can be used as a sensitive probe of new interactions or to measure subtle nuclear effects. Elementary particles such as electrons and quarks (which make up protons and neutrons) carry intrinsic angular momentum called spin and act much like spinning tops. By convention, particles spinning clockwise with respect to their direction of motion are said to be lefthanded, whereas their mirror images — those

spinning anticlockwise — are right-handed. Parity symmetry swaps left and right, just as a mirror does. Gravity, electromagnetism and strong nuclear forces all respect parity; that is, they are symmetrical (unchanged) under left–right interchanges. However, in 1956, Tsung-Dao Lee and Chen-Ning Yang conjectured2 that the weak forces responsible for nuclear decays and neutrino interactions might violate parity. Subsequent experiments not only confirmed that feature, but also found that parity violation was maximal: only left-handed particles experienced the weak interaction; right-handed particles were not affected by the weak forces that were known then. Antiparticles, such as antielectrons and antiquarks, exhibited the opposite preference — only their right-handed components participated in weak interactions. For the revolutionary idea of parity violation, Lee and Yang received the physics Nobel prize in 1957. Beyond parity violation, small differences between the weak interactions of left-handed particles and those of right-handed antiparticles, known as CP violation or matter– anti­matter asymmetry, were subsequently observed3. Today, some as yet undiscovered

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RESEARCH NEWS & VIEWS form of CP violation is thought to be responsible for the dominance of matter over antimatter throughout the Universe — a feature responsible for our very existence. Symmetry violation can, indeed, have profound consequences. Apart from parity violation, electromagnetic and weak interactions are quite similar. Both can be viewed as exchanges of packets (quanta) of energy called bosons. Electromagnetism is mediated by massless photons, whereas heavy, charged W bosons mediate weak inter­actions. Although some sort of electroweak unification, jointly describing both inter­actions, seemed natural4, parity violation caused problems. In 1961, it was shown5 that unification was possible if, in addition to charged W bosons, another heavy neutral boson, now called the Z boson, also existed. Unfortunately, even then, parity violation made it difficult to accommodate or relate elementary-particle masses. The problem was solved in 1967, when it was demonstrated6 how the introduction of symmetry breaking through the Higgs mechanism could be used to provide mass. A predicted remnant of that mechanism — the Higgs boson — was detected in 2012 at CERN, Europe’s high-energy physics laboratory near Geneva, Switzerland, and François Englert and Peter Higgs were awarded last year’s Nobel Prize in Physics for the theoretical work on the Higgs mechanism. In the early 1970s, support for the existence of the Z boson was observed in neutrinoscattering experiments7. But follow-up studies proved inconclusive, in that they did not confirm the parity-violating predictions of electroweak unification. Then an experiment8,9 called E122, conducted at the SLAC National Accelerator Laboratory in Menlo Park, California, measured a small parity-violating difference between the scattering of right- and left-handed electrons on up and down quarks in a target of deuterium atoms. The up and down quarks are the lightest of the six possible types of quark, and make up all nuclei. This result unequivocally confirmed the parityviolating predictions of electroweak unification. For their work on electroweak unification and its implications, Sheldon Lee Glashow5, Abdus Salam10 and Steven Weinberg6 received the physics Nobel prize in 1979. During the 35 years since E122 was completed, better sources of right- and left-handed electrons have been developed, experimental techniques have improved and more-intense electron beams have become available. Parity violation has been used for the precise measurement of para­meters that describe the electro­weak inter­action and to investigate nuclear properties. But the parity-violating difference measured in the E122 experiment has not been improved on — until now. In their study, the Jefferson Lab team decided to redo the SLAC E122 experiment. The researchers worked at lower energy but with much higher intensity and polarization

(degree of handedness). As a result, they improved on some aspects of parity-violating differences between the scattering of right- and left-handed electrons on up and down quarks by about a factor of five. With their higher statistics, they were able to untangle the two parity-violating effects: the dominant effect due to electron parity violation, which had already been clearly measured in E122, and a much smaller parity-violating effect attributable to the quarks in the deuterium nuclei, which was beyond the sensitivity of the SLAC experiment. Why measure such small effects, and so precisely? Perhaps, like mountain-climbing enthusiasts, physicists study them because they are there and represent challenges. However, unlike mountains, in the case of parity-violating effects sometimes smaller is better. Testing the tiny quark parity-violation prediction is a nice example: a deviation from expectations could signal the presence of a new tiny effect. Indeed, the team’s measurement probes some types of additional parity-violating effects that could be as much as 30 times weaker than ordinary weak forces. Precision studies also provide access to small nuclear effects that are hard to probe in other ways. An example is the breaking of charge symmetry (the interchange of up and down quarks in deuterium). Parity-violating polarized electron scattering experiments are expected to continue at the Jefferson Lab, using higher-energy electrons and better particle-detection systems, after upgrades to the facility, now in progress, are completed. One can anticipate better measurements of electroweak parameters,

more-refined nuclear-physics studies and improved searches for new interactions. A great accomplishment can lead to the demise of a scientific endeavour. A good example is the race to put a man on the Moon. That goal started more than 50 years ago and was a spectacular success, but further undertakings ended after the mission was accomplished. Fortunately, electron-scattering studies of parity violation did not suffer that fate. Following the success of E122 at SLAC, the programme changed direction, but improvements in technical expertise and accelerator facilities continued. The Jefferson Lab has taken leadership in polarized-electron scattering initiatives. As long as these initiatives address frontier questions and interesting goals, they should prosper and grow. ■ William J. Marciano is at the Brookhaven National Laboratory, Upton, New York 11973, USA. e-mail: [email protected] 1. The Jefferson Lab PVDIS Collaboration Nature 506, 67–69 (2014). 2. Lee, T. D. & Yang, C. N. Phys. Rev. 104, 254–258 (1956). 3. Christenson, J. H., Cronin, J. W., Fitch, V. L. & Turlay, R. Phys. Rev. Lett. 13, 138–140 (1964). 4. Schwinger, J. Ann. Phys. 2, 407–434 (1957). 5. Glashow, S. L. Nucl. Phys. 22, 579–588 (1961). 6. Weinberg, S. Phys. Rev. Lett. 19, 1264–1266 (1967). 7. Hasert, F. J. et al. Phys. Lett. B 46, 138–140 (1973). 8. Prescott, C. Y. et al. Phys. Lett. B 77, 347–352 (1978). 9. Prescott, C. Y. et al. Phys. Lett. B 84, 524–528 (1979). 10. Salam, A. Conf. Proc. C680519, 367–377 (1968).

EC O LO GY

Plant diversity rooted in pathogens Ecologists have long pondered how so many species of plant can coexist locally in tropical forests. It seems that fungal pathogens have a central role, by disadvantaging species where they are locally common. See Letter p.85 HELENE C. MULLER-LANDAU

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ropical forests routinely contain more than 200 tree species in a single hectare (Fig. 1). Why don’t a few species come to dominate, by chance or by virtue of being better competitors? Multiple hypotheses have been proposed to answer this question, most of which invoke some sort of niche differentiation with respect to resources and/or natural enemies. But despite decades of research, the issue remains unresolved. In this issue, Bagchi et al.1 (page 85) report the results of an elegant field study that clearly

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implicates natural enemies, specifically fungal pathogens, as crucial to maintaining tropicalplant diversity. In 1970, ecologists Daniel Janzen2 and Joseph Connell 3 proposed that natural enemies that target specific host plants maintain high tropical-plant diversity by elevating the mortality of each plant species in areas where it is abundant. Fundamentally, the idea is that host-specialized enemies, including pathogens and insect herbivores, can attack more efficiently and do more damage where their hosts are more plentiful. As a result, each host species fares better when it is