immunology: professional secrets
TRANSCRIPT
Our immune system provides effectiveprotection against most pathogens.It can mount a highly specific ‘adap-
tive’ response that distinguishes between different sorts of pathogen and activates the appropriate mechanisms to eliminatethem. Writing in this issue, Amigorena andcolleagues1 and Desjardins and colleagues2
suggest how an adaptive immune responsetypically reserved for pathogens that repli-cate inside immune cells can also be gener-ated against pathogens that exist outsidethese cells.
Macrophages and dendritic cells are specialized cells that initiate adaptiveimmune responses. They are sometimescalled professional antigen-presenting cells(APCs) because one of their primary dutiesis to degrade microbial proteins and displaythe resulting peptide fragments, or antigens,on their surface. The kind of immuneresponse that is then produced depends onhow the antigens are displayed by the APCs.
In general, peptide antigens from patho-gens replicating inside APCs (endogenousantigens) are transported into a cellular com-partment, the endoplasmic reticulum (ER),and bind to a protein complex called MHCclass I.From the ER,the MHC class I–antigencomplex is shuttled to the cell surface, whereit stimulates antigen-specific cytotoxic Tlymphocytes (CTLs) — killer cells that seekout and eliminate infected cells (Fig.1).
Antigens from extracellular pathogens areusually processed differently from endogen-ous antigens,and with different results.Extra-cellular pathogens are engulfed by APCs anddegraded in phagosomes — membrane-bound cellular compartments. Peptide frag-ments produced in phagosomes are not trans-ported to the ER.Instead,they bind directly toa different set of MHC molecules, MHC classII, inside the phagosome and then return tothe cell surface, where they stimulate a subsetof helper T cells (Fig. 1). Unlike the CTLs,helper T cells do not kill other cells,but insteadproduce chemical signals. These trigger theproduction of antigen-specific antibodiesand elicit an inflammatory response thateliminates the microbial pathogens.
So the rules governing antigen presenta-tion seem to be simple — endogenous anti-gens are presented by MHC class I moleculesto stimulate a cell-killing response, andexogenous antigens are presented by MHCclass II molecules to stimulate a helper
response. But in reality, the situation is not so straightforward. Professional APCs canbreak these rules and present exogenousantigens on MHC class I molecules3, in aprocess known as cross-presentation. Thecross-presentation pathway seems to berequired for CTL responses to certain exoge-nous antigens4,5. For example, some virusesdo not infect professional APCs, but in order to generate a CTL response that willeliminate virus-infected cells, the APC mustpresent exogenous viral proteins on MHCclass I molecules. Cross-presentation mightalso be important for triggering CTLresponses to some cancer cells.
So how do exogenous antigens cross overto the MHC class I pathway? Amigorena and colleagues had previously shown6 thatexogenous proteins could escape fromphagosomes and enter the cytosol (the intracellular space). So it was thought thatcross-presentation might simply involve thetransport of exogenous proteins from thephagosome into the cytosol, where they
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could join the pathway used to processendogenous antigens. This view was sup-ported by data7,8 showing that cross-presen-tation depends on two components of theMHC class I pathway — the proteasomecomplex and the ‘transporter associated withantigen presentation’ (TAP). The protea-some complex degrades proteins in thecytosol and TAP shuttles the resulting peptide antigens into the ER for loading onto MHC class I molecules. Furthermore,cross-presentation is sensitive to the drugbrefeldin A (refs 7, 8), which disrupts thetransport of the MHC class I–antigen com-plex from the ER to the cell surface9.
Desjardins and colleagues, meanwhile, hadprovided a clue to how exogenous antigensmight escape from the phagosome10,11. In aneffort to understand how phagosomes formand mature, these authors had catalogued theproteins contained on phagosomes that hadbeen purified from macrophages.Surprisingly,they detected proteins that were thought toreside only in the ER10. Further analysis
Professional secretsCraig R. Roy
Looking inside the compartments of certain immune cells — professionalantigen-presenting cells — has revealed how the immune system can trigger a cell-killing response to extracellular pathogens.
ExogenouspathwayAntigen
presentationto CTLs
Antigenpresentation
to helperT cells
Extracellularpathogen
Phagosome
Nucleus
Endoplasmicreticulum
Virus
Viralproteins
Cross-presentation?
Endogenouspathway
MHC class ITAPProteasomeMHC class II
Figure 1 Professional antigen-presenting cells process intracellular and extracellular pathogensdifferently. In the endogenous pathway, proteins from intracellular pathogens, such as viruses, aredegraded by the proteasome and the resulting peptides are shuttled into the endoplasmic reticulum(ER) by TAP proteins. These peptides are loaded onto MHC class I molecules and the complex isdelivered to the cell surface, where it stimulates cytotoxic T lymphocytes (CTLs) that kill the infectedcells. In contrast, extracellular pathogens are engulfed by phagosomes (exogenous pathway). Insidethe phagosome, the pathogen-derived peptides are loaded directly onto MHC class II molecules,which activate helper T cells that stimulate the production of antibodies. But some peptides fromextracellular antigens can also be ‘presented’ on MHC class I molecules. How this cross-presentationoccurs has now been explained1,2. It seems that by fusing with the ER, the phagosome gains themachinery necessary to load peptides onto MHC class I molecules (see Fig. 4g on page 405).
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revealed that phagosomes fused with the ERduring, or shortly after, pathogen engulfmentat the cell surface11.This was an important find-ing because a protein-translocation channelcalled the Sec61 complex is embedded in theER membrane. Sec61 both imports newly synthesized proteins into the ER and exportsproteins from it, targeting the proteins fordegradation by the proteasome12,13. So it waspredicted that the Sec61 complex might bedelivered to the phagosome after fusion withthe ER.If true,it could be the missing link in thecross-presentation pathway — the transporterresponsible for exporting exogenous proteinsfrom the phagosome into the cytosol.
The two groups1,2 now provide evidenceto support this hypothesis. Looking atphagosomes from dendritic cells1 andmacrophages2,respectively,they showed thatSec61 is indeed present on the phagosomemembrane. And both groups found that afluorescently tagged version of the proteinovalbumin could be exported from thephagosome into the cytosol. But did proteinexport involve Sec61? To find out,Desjardinsand colleagues looked at the export of thecholera toxin A1 subunit (CTA1). This pro-tein moves from outside the cells to the ERand is then exported from the ER into thecytoplasm through the Sec61 channel14,15.The authors observed that CTA1 could alsobe exported from the phagosome into thecytoplasm, which strongly suggests that,after Sec61 is delivered to the phagosome, itcan still export proteins.
What happens to proteins once they havebeen exported from the phagosome? First,they must be turned into peptide antigens by the proteasome. Desjardins and colleagesshowed that proteasomes are associated withthe cytosolic side of the phagosome mem-brane. And both groups showed that TAPand the MHC class I molecules are deliveredto the phagosomes and remain active. Theirfurther analyses revealed that the peptideantigens are loaded onto MHC class I mol-ecules inside the phagosome.
So it seems that after the exogenous proteins are exported from the phagosomethrough the Sec61 channel,they are degradedby the proteasome and the resulting peptideantigens are shuttled back into the phago-some by TAP. There, they are loaded ontoMHC class I molecules on the inside of thephagosome membrane. The results confirmobservations16 that the phagosome is a fully competent antigen-processing com-partment for the MHC class I pathway.
The new studies provide strong supportfor a model of cross-presentation in whichER–phagosome fusion occurs. But they donot show that such fusion is necessary.Argu-ments have also been made that cross-presentation occurs only in cultured cellsand might not be relevant in animals17.Now that a molecular mechanism govern-ing cross-presentation has been proposed,
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experiments to test the importance of thisimmunological process are certain to follow.But the debate on cross-presentation con-tinues — to resolve it, the professionals willhave to reveal all of their secrets. ■
Craig R. Roy is in the Section of MicrobialPathogenesis, Yale University School of Medicine,New Haven, Conneticut 06536, USA.e-mail: [email protected]. Guermonprez, P. et al. Nature 425, 397–402 (2003).
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Plasma physics
Cosmic waves in the labRod Boswell
An Alfvén-wave maser, a feature of atmospheric and astrophysicalscience, has been created in a laboratory, and opens the way forfurther Earth-bound investigations of cosmic phenomena.
In general, to be an observational astron-omer is to be a spectroscopist, unravellingthe workings of the cosmos through the
varying wavelengths of radiation detected.Observations that began at optical wave-lengths now extend to wavelengths rangingfrom hundreds of kilometres down to tensof nanometres, and satellites have alsoproved immensely useful in refining ourimage of the Universe. But, despite theassiduous measurements, the radiation isoften produced, particularly at radio and X-ray wavelengths, by very complex pro-cesses that we struggle to understand.Nevertheless, a positive step has now beentaken: in Physical Review Letters, J. E. Maggsand G. J. Morales report the resonantamplification of a typical astrophysical wavein their laboratory — an Alfvén-wave maser
(Phys. Rev. Lett. 91, 035004; 2003).For some years, the aim of these authors
has been a laboratory study of magneto-hydrodynamic turbulence — that is, turbu-lence in the interactions between a plasma anda magnetic field. The first step on the way is tocreate the basic element of the phenomenon,an Alfvén wave.Postulated in 1942 by HannesAlfvén (Nature 150, 405–406; 1942), anAlfvén wave is a low-frequency electromag-netic wave that can be generated in magne-tized plasmas throughout the Universe.Thesewaves are thought to be intimately involved indiverse phenomena, such as the precipitationof electrons through the atmosphere in theauroral regions that are connected with thedazzling northern and southern lights — andthat can take out power distribution systems.Alfvén waves are also implicated in the heating
Figure 1 Unique facility — the Large Plasma Device at the University of California, Los Angeles.In a helium plasma inside this 19-metre-long column of magnets, Maggs and Morales have created an Alfvén-wave maser.
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