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the transition temperature in the case ofyttrium–barium–copper oxides, and Tc isclaimed to be independent of distance5 inBiSCCO, a particular bismuth compound.So the question of what transition tempera-ture a single CuO2 plane would have is stillunsolved.

The present results1 clearly demonstratethat the application of large uniaxial straincan increase superconducting transitiontemperature by a substantial factor, and per-haps this technique can be extended to othersuperconductors and lead to even highertransition temperatures.

Practical devices based on thin films arealways grown on properly chosen substrates.

Thus a judicious choice of substrates couldconsiderably benefit applications using filmsthat are thin enough to be subject to largeepitaxial strains.Ivan K. Schuller is in the Physics Department,University of California at San Diego, La Jolla,California 92093-0319, USA.e-mail: ischuller@ucsd.edu

1. Locquet, J.-P. et al. Nature 394, 453–456 (1998).

2. Falicov, L. M. et al. J. Mater. Res. 5, 1299 (1990).

3. Dhez, P. & Weisbuch, C. (eds) Physics, Fabrication and

Applications of Multilayered Structures (Plenum, New York,

1988).

4. Shinjo, T. & Ono, T. J. Mag. Mag. Mater. 177, 31 (1998).

5. Choy, J. H., Kwon, S.-J. & Park, G.-S. Science 280, 1589–1592

(1998).

6. Chakravarty, S. et al. Science 261, 337–340 (1993).

tion, might activate memory B cells that arespecific for the original virus (although it isnot clear why antibodies specific for the newvariant are not stimulated too). In the sameway, the phenomenon observed by Klener-man and Zinkernagel3 might reflect the verystrong CTL memory response to LCMVinfection. Studies7–9 of acute LCMV infec-tion in mice showed that massive CTLresponses occurred, whereby 25–50% of allCD8-positive T cells were virus specific. Evenafter recovery, 10% of peripheral CD8-positive T cells were specific for theimmunodominant LCMV epitopes. A weak-ly cross-reacting new virus might, therefore,reactivate these plentiful CTL memory cellsmore readily than the much less abundantnaive CTL precursors (Fig. 1). Although thismechanism depends on very high levels ofmemory CTLs, similar numbers are seen inpersistent HIV infection10, where originalantigenic sin may also occur4,5.

A second possibility is that activatedmemory CTLs remove enough of the anti-gen-presenting cells (APCs) to abort the pri-mary CTL response to the new viral epitope.This would be consistent with the delayedclearance of mutant compared with wild-type virus in secondary challenges. Thememory CTL could simply kill the APC,although recent results11–13 indicate anotherpossibility. A type of APC called the dendrit-ic cell must be activated in order to initiateCTL responses. Activation occurs throughan interaction between the CD40 ligand onT helper cells and CD40 on the dendriticcells. But if this requirement for activateddendritic cells is less stringent for the memory CTLs, these CTLs could deactivatethe dendritic cells, thereby inhibiting new

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The phrase ‘original antigenic sin’ wasfirst used to describe the antibodyresponse to influenza virus. After an

initial infection, reinfection (or vaccination)with a new strain of the virus boosted theconcentration of antibodies specific for theearlier infecting strain1,2. Although theseantibodies cross-reacted with the new virus,they had higher affinity for the originalinfecting strain. This was immediately seento have big implications for vaccine design— a vaccine based on a new strain of influen-za virus might be unable to prime antibodiesto the intended virus in people who hadalready been infected with a related viralstrain.

Until now, original antigenic sin hasbeen regarded as largely an antibodyphenomenon. But, on page 482 of this issue, Klenerman and Zinkernagel3 describeoriginal sin in the response of cytotoxic T lymphocytes (CTLs) to lymphocyticchoriomeningitis virus (LCMV). Theirwork was stimulated by studies of peoplewith the human immunodeficiency virus(HIV), who sometimes mount a CTLresponse to an immunodominant strain ofthe virus with weak or no response to theother immunogenic variants present4,5.

The authors attacked the problem in vivo.They infected mice with strains of LCMVthat were either normal (wild type) ormutated at the immunodominant epitopesrecognized by the CTL. For each mutatedstrain studied, they found that the CTLresponse was asymmetrical. Mice infectedwith the wild-type virus showed only a weakcross-reactive specificity when challengedwith the mutant strain, reacting mainly tothe wild-type virus. The low reactivity ofCTLs against the mutant strain was alsoassociated with delayed clearance of this

strain by the immune system. In contrast, the CTL responses from mice infected withthe mutant virus cross-reacted equally withthe mutant and wild-type strains. Thus, theorder in which the mice are exposed to differ-ent variants of the virus could have a signifi-cant effect on the outcome of the infection.

How does this happen? A possible expla-nation6 for antibody original antigenic sinemerged when helper T cells were discov-ered, and it was realized that T cells react withpeptide fragments of viral proteins that areoften conserved between different strains.So, helper T cells, primed by the originalvirus and then stimulated by the new infec-

Immunology

The original sin of killer T cellsAndrew J. McMichael

Figure 1 Original antigenic sin in cytotoxic T lymphocytes (CTLs). Klenerman and Zinkernagel3 havediscovered that the phenomenon of original antigenic sin — whereby infection with a virus booststhe concentration of antibodies against a related strain from a previous infection — also occurs in theresponse of CTLs. Memory CTLs stimulated by wild-type antigen (blue) are abundant and, althoughweakly stimulated through their receptors, can kill or inhibit antigen-presenting cells (APCs)presenting the variant virus (red). Persisting APCs that present the wild-type virus may partiallyactivate and antagonize naive T cells specific for the variant virus.

Variant-virus-infected APC

Kill?Memory

CTL(1 in 10 cells)

Naive CTL(1 in 106 cells)

Wild-type specific

Variant specific

Inhibit?

Antagonize?

Wild-type-virus-infected APC

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control of variable viruses such as HIV andhepatitis C virus. Original antigenic sinmeans that a monovalent vaccine (such as apeptide) intended to stimulate CTLs maynot work if the virus varies at that epitope.Not only would the vaccine-induced CTLresponse fail to control infection with anyvariant virus, but the CTL response to theequivalent epitope in that virus might also beimpaired. The vaccine might even make theinfection worse. The probable solution is tochoose several well-conserved epitopes forthe vaccine — but HIV is so variable, thesemay be in short supply.Andrew J. McMichael is at the Institute of MolecularMedicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.e-mail: amcmichael@hammer.imm.ox.ac.uk1. Francis, T. Ann. Int. Med. 39, 203–221 (1953).

2. Fazekas de St Groth, S. & Webster, R. G. J. Exp. Med. 124,

331–346 (1966).

3. Klenerman, P. & Zinkernagel, R. M. Nature 394, 482–485

(1998).

4. McAdam, S. N. et al. J. Immunol. 155, 2729–2736 (1995).

5. Klenerman, P., Meier, U. C., Phillips, R. E. & McMichael, A. J.

Eur. J. Immunol. 25, 1927–1931 (1995).

6. Askinas, B. A., McMichael, A. J. & Webster, R. G. in Basic and

Applied Influenza Research (ed. Beare, A. S.) 157–188 (CRC

Press, Boca Raton, FL, 1982).

7. Butz, E. & Bevan, M. Immunity 8, 167–175 (1998).

8. Gallimore, A. et al. J. Exp. Med. 187, 1383–1393 (1998).

9. Murali-Krishna, K. et al. Immunity 8, 177–187 (1998).

10.Ogg, G. S. et al. Science 279, 2103–2106 (1998).

11.Bennett, S. R. M. et al. Nature 393, 478–480 (1998).

12.Ridge, J. P., DiRosa, F. & Matzinger, P. Nature 393, 474–478

(1998).

13.Schoenberger, S. P., Toes, R. E. M., van der Voort, E. I. H. &

Melief, C. J. M. Nature 393, 480–483 (1998).

14.Lalvani, A. et al. J. Exp. Med. 186, 859–865 (1997).

15.Meier, U.-C. et al. Science 270, 1360–1362 (1995).

16.Klenerman, P., Hengartner, H. & Zinkernagel, R. M. Nature

390, 298–301 (1997).

17.Haas, G. et al. J. Immunol. 157, 4212–4221 (1996).

18.Harrer, T. et al. J. Immunol. 156, 2616–2623 (1996).

more than just the geologists in the crowd.Generally, the characteristics of these

abrupt climate shifts implicate changes inlarge-scale ocean circulation as the culprit:the atmosphere adjusts to perturbation tooquickly and does not have the ‘memory’required to drive millennial-scale variabili-ty; the solid Earth (including polar ice), onthe other hand, reacts too slowly. There areconceivable exceptions to this generaliza-tion. For example, glacial processes could be involved, because some ice sheets areinherently unstable and are prone tosurging2. Also, the possibility of externalinfluences, such as changes in solar lumi-nosity or tidal energy, cannot be discounted.However, even unstable ice sheets mustrespond to some initial climate disturbance,and so glacial processes are themselves probably not the primary agent of change.And any connection with external forces isextremely difficult to prove or test.

If the answer lies in the ocean, then whataspect of ocean circulation could suddenlyalter the global climate system, after operat-ing normally for more than a thousandyears? The most widely recognized hypoth-esis has been that the formation of NorthAtlantic Deep Water — a process by whichwarm surface currents lose their heat to theatmosphere and sink to fill the deep oceanbasin — flipped between two stable modesof operation. For climate purposes, thesemodes are essentially ‘on’ or ‘off ’3. The cli-matic effect of such a change might be signif-icant: deepwater formation around Green-land today brings oceanic heat northward,making much of Europe several degreeswarmer than it probably would be other-wise. And, as a water mass, North AtlanticDeep Water acts to redistribute heat and saltglobally.

Furthermore, there is ample evidencefrom deep-sea sediment cores (much ofwhich was presented at the conference)showing that sinking processes in the NorthAtlantic did in fact undergo millennial-scaleoscillations similar to those inferred fromclimate records such as the Greenland icecores (for an example, see ref. 4). So thismechanism, popularly known as the ocean’s‘conveyor belt’, could explain the observa-tions of abrupt climate change from theentire circum-Atlantic region. It also mightexplain the connection between the severityof the abrupt shifts and the presence of icesheets, if the continental ice had a varyinginfluence on the density (the tendency forsinking) of North Atlantic surface waters.

The problem with this seemingly tidypackage is that, to drive fluctuations in glob-al temperature, either the greenhouse capac-ity or the reflectivity (albedo) of the planetmust be affected. And without invokingcomplicated feedbacks, it is not clear fromgeneral principles that the North Atlanticcirculation has the climatic influence to

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422 NATURE | VOL 394 | 30 JULY 1998

primary CTL responses. Deactivation couldoccur through the interferon-g and othercytokines that are released from memoryCTLs within a few hours of contact withantigen14.

Another explanation would be that aform of T-cell-receptor antagonism occurs15.If the CTL clones that react with the mutantviral epitope have receptors that bind sub-optimally to the wild-type epitope, the resultmight be partial activation, leading to anergy(a failure of the immune system to respond).Thus, the wild-type virus would antagonizethe primary CTL response to the mutantstrain. For this mechanism to work, antigenfrom a previous infection would need to persist. Low levels of integrated DNA persistin mice infected with LCMV16, althoughthese levels are probably too low for antago-nism to occur. Moreover, in Klenerman andZinkernagel’s study, the CTLs stimulated by the mutant virus cross-reacted well with the wild-type virus, arguing against thisexplanation.

Original antigenic sin in CTL responsescould be very important — it could explainsome of the complexity in CTL responses toHIV and its variants17,18. If it were a commonphenomenon, it would give viruses anothermeans of escape from the immune system.That is, once a high-level CTL response hasbecome fixed, immunogenic mutants mightescape and become dominant in the swarmof viral quasispecies, failing to provoke aneffective CTL response.

Just as in the initial description of originalantigenic sin, the new work3 has implicationsfor vaccine design. Many groups are now try-ing to design CTL-inducing vaccines for the

If geologists were to construct ‘top ten’ lists of the advances of the century, the relatively recent discovery that the Earth

has switched repeatedly and abruptlybetween cold and warm climates over thecourse of ice-age cycles would no doubt feature prominently. Yet, despite the decadeof research devoted to characterizing this so-called ‘millennial-scale’ climate variabili-ty, there are still primary questions about theorigin of such abrupt changes and, therefore,equal uncertainties in predicting how climate might behave in the future. Thesequestions surfaced last month at an Ameri-can Geophysical Union conference*, where afew scientists challenged established dogmacentred on the North Atlantic by suggestingthat the tropical Pacific may have been

involved — a fitting proposal in a year whenEl Niño took the blame for a variety ofhuman woes.

The conference objective was to discussthe climate processes that may explain theinferences from archives such as ice cores anddeep-sea sediment cores — temperatureswings of up to 10 °C, spaced several thou-sand years apart, occurring over much of theEarth’s surface but more violently when theEarth was in a partly or fully glaciated state.The disquieting feature of these climatechanges is that the switch between cold andwarm conditions apparently happened in aslittle as 20 years1. Identifying the processesresponsible would help assess the likelihoodof climate ‘surprises’ associated with globalwarming. And obviously, any similar climateshifts occurring in the near future wouldhave profound repercussions for Earth’shabitability. So the subject was of interest to

Palaeoclimatology

The ends of an eraChristopher Charles

*Chapman Conference on Mechanisms of Millennial-Scale Global

Climate Change, Snowbird, Utah, 14–18 June 1998.

http://www.agu.org/meetings/cc98dcall.html