death, destruction, danger and dendritic cells

THE ACTIVATION OF dendritic cells (DCs) isa crucial step in the initiation of

many adaptive, or lymphocyte-medi-ated, immune responses. DCs are antigenpresenting cells that serve to recognizeand internalize foreign infectious anti-gens1,2. They exist in a quiescent state inmost tissues, but certain stimuli triggerDC to become mature or activated, suchas microbial products and inflammatorycytokines. Probably after activation, in-ternalized antigens are degraded intopeptides, which are bound to MHC mol-ecules and transported to the cell surfacefor recognition by T cells. It was recentlydiscovered that activated DCs also havethe capacity to deliver the co-stimulatorysignals required for T-cell activation, andhence the generation of adaptive re-sponses, and the ability to migrate from

non-lymphoid locations into centrallymphoid tissues where such responsesare initiated.

Because DCs are so potent at initiatingimmune responses, there is considerableinterest in using or targeting these cellsfor therapeutic purposes, for example, toenhance antimicrobial vaccinationstrategies or to stimulate anti-cancer re-sponses1,2. The latter possibility is alreadybeing addressed in a number of clinicalstudies. Conversely, it is also possiblethat DC could be either used or targetedto turn off immune responses, such asthose that occur in allergic reactions, au-toimmune diseases or transplantation re-jection. This possibility arises because

presentation of peptide–MHC complexesto resting T cells in the absence of co-stimulatory signals can lead to deletionor inactivation of these T cells, andhence a state of tolerance. Whether ornot DCs are activated, and hencewhether or not they express the relevantco-stimulatory molecules, could thus becrucial, at least in part, in determiningthe outcome of their interaction with Tcells. It is therefore most important thatwe gain a better understanding of thestimuli that activate DCs, a topic ad-dressed in a paper by Matzinger and col-leagues3 in this issue of Nature Medicine.

There are different views as to the na-ture of DC-activating stimuli. Arguably,these views need not be mutually exclu-sive. The immune system has evolvedthe ability to discriminate between self

JONATHAN M. AUSTYN

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ing from the release of cellular compo-nents, and prevent autoimmune reac-tions to self proteins. Recent studies onimmune privileged sites, however, haveshown that this may not always be true.In these studies, the death of lymphoidcells within the eye led directly to ananti-inflammatory response that down-regulated systemic immunity10.

The question then becomes, how doapoptotic cells regulate the immune re-sponse? Again, a lesson from the ‘privi-leged’ site may be useful11. Lymphocytesinduced to undergo apoptosis (throughFas or other mechanisms) produce theanti-inflammatory cytokine IL-10 asthey die. Phagocytosis of these apoptoticcells along with antigen leads to antigenpresentation in tolerogenic form. Thisresults in systemic immune tolerance inthe form of immune deviation to anyantigens presented by these presentingcells. The immunoregulatory capacity ofapoptotic cells has also been demon-strated in other systems12,13 in whichphagocytosis by macrophages led to theproduction of inhibitory cytokines (suchas IL-10 and TGF-β). These results showthat apoptotic cell death and immunetolerance are linked through the activa-tion of immunoregulatory mechanismsmediated by inhibitory cytokines. Thus,

promoting apoptosis not only deletes re-active cells, it also promotes active regu-latory pathways through the inhibitoryproperties of apoptotic cells. The toler-ance is now stable because of a doublehit—deletion and regulation. In themidst of death, lymphocytes can influ-ence the immune response and help es-tablish immune tolerance.

Of course, most of us believe that thebest graft-destroying lymphocyte is adead graft-destroying lymphocyte, butit is possible that apoptotic cells pro-mote graft tolerance even from beyondtheir graves. Understanding preciselyhow this may happen will help to fur-ther our quest for transplantation toler-ance that can be used in the clinic.

1. Lenardo, M. et al. Mature T lymphocyte apopto-sis–Immune regulation in a dynamic and unpre-dictable antigenic environment. Ann. Rev.Immunol. 17, 221–253 (1999).

2. Griffith, T.S. et al. Fas-Ligand-induced apoptosisas a mechanism of immune privilege. Science270,1189–1191 (1995).

3. Stuart, P.M. et al. CD95 ligand (FasL)-inducedapoptosis is necessary for corneal allograft sur-vival. J. Clin. Invest. 99, 396–402 (1997).

4. Li, Y. et al. Global immunosuppression preventsapoptosis of alloreactive T cells and induction ofperipheral allograft tolerance. Nature Med. 5,1298–1302 (1999).

5. Wells, A.D. et al. Requirement for T-cell apoptosisin the induction of peripheral transplantation tol-erance. Nature Med. 5 1303–1307 (1999).

6. Larsen, C.P. et al. Long term acceptance of skin

and cardiac allografts after blocking CD40 andCD28 pathways. Nature 381, 434–438 (1996).

7. Kirk, A.D. et al. Treatment with humanized mono-clonal antibody against CD154 prevents acuterenal allograft rejection in nonhuman primates.Nature Med. 5, 686–693 (1999).

8. Brunner, T. et al. Cell-autonomous Fas(CD95)/Fas-ligand interaction mediates activa-tion-induced apoptosis in T-cell hybridomas.Nature 373, 441–444 (1995).

9. Li, X.C. et al. Induction of allograft tolerance in theabsence of Fas-mediated apoptosis. J. Immunol.163, 2500–2507 (1999).

10. Griffith, T.S. et al. CD95-ligand induced apoptosisof lymphocytes in an immune privileged site in-duces immunologic tolerance. Immunity, 5, 7–16(1996).

11. Gao, Y. et al. The anti-inflammatory effects ofCD95 ligand (FasL) induced apoptosis. J. Exp.Med. 188, 887–896 (1998).

12. Fadok V.A. et al. Macrophages that have ingestedapoptotic cell in vitro inhibit proinflammatory cy-tokine production through autocrine/paracrinemechanisms involving TGF-beta, PGE2, and PAF. J.Clin. Invest. 101, 890–898 (1999).

13. Ronchetti, A. et al. Immunogenicity of apoptoticcells in vivo: role of antigen load, APC and cy-tokines. J. Immunol. 163, 130–136 (1999).

1Department of Ophthalmology and VisualSciences, 660 S. Euclid, Box 8086Washington University School of MedicineSt. Louis, Missouri 63110Email: ferguson@am.seer.wustl.edu2Division of Cellular ImmunologyLaJolla Institute of Allergy and Immunology10355 Science Center DriveSan Diego, California 92121Email: dgreen5240@aol.com

Death, destruction, danger and dendritic cellsDendritic cells are known to be involved in recognition of foreign antigens and initiation of specific

T-cell responses. The ‘danger hypothesis’ suggests that the immune system can also respond toendogenous signals of distress. New data indicate that dendritic cells are the first to respond to

these signals, although the mechanisms involved in their activation are unclear (pages 1249–1255).

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and infectious non-self4. According tothis view, DCs could be activated by in-teraction with infectious agents from theexternal world. This fits nicely with aconsiderable body of evidence that mam-malian cells, including DC, have ‘patternrecognition receptors’ that can recognizemicrobial components not normally pro-duced by vertebrates. Structurally andfunctionally related receptors are in factconserved throughout evolution, beingalso present for example in insect andplant cells. Exogenous agents known toactivate DCs include lipopolysaccharidesand teichoic acids of bacterial cell walls,non-methylated CpG motifs in bacterialand synthetic DNA, and double-strandedRNA of viral genomes2.

An alternative view of DC-activatingstimuli is based on the hypothesis, putforward by Matzinger and colleagues afew years ago, that the immune systemdiscriminates between what does or doesnot present ‘danger’—roughly speaking5,what does or does not pose a threat tothe organism. According to this view,DCs could be activated to respond to in-ternal injury through endogenous medi-ators. But what might these stimuli be?In the current paper, the authors nicelydemonstrate that necrotic cells co-cul-tured with DCs can actually activateDCs. In contrast, living or apoptotic cellsdo not activate DCs.

Taken at face value, this theory makessense—DC become activated when tis-sues are damaged or ‘stressed’, eventsthat could signify the presence of infec-tion. On the other hand, apoptotic celldeath is a normal physiological processinvolved in normal biological processessuch as tissue remodelling. The lack of‘danger’ in this case would preclude theneed to activate adaptive immunity. Oneimportant question is to what extent thefindings in the current paper, madeusing ceramide-induced apoptotic cells

or frozen and thawed necrotic cells forexample, can be applied to the in vivo sit-uation. Further research will be requiredto answer this question.

Many of the findings reported byMatzinger and colleagues are at variancewith data from other investigators. Forexample, previous studies have shownthat apoptotic cells can in fact trigger DCactivation6. Also, the authors report theinability to detect presentation to a T-cellclone of an antigen (H-Y) from the apop-totic cells on MHC class II molecules.However, prior reports have clearlydemonstrated that antigens from virallyinfected apoptotic cells can be presentedon MHC class I molecules to cytotoxic T-lymphocyte clones7, and in another caseon MHC class II by DCs in vivo 8. It is pos-sible that antigens from apoptotic cells,perhaps including normally sequesteredself antigens, can be presented by DCs,but that DCs do not become activated.Therefore, it is possible that these DCstolerize T cells (antigen presentation inthe absence of co-stimulation). Certainlythere is good evidence for a bone mar-row-derived cell that is responsible notjust for ‘cross-priming’ but also for ‘cross-tolerance’9.

A vexing question, however, is howand where such tolerance is induced. Ifactivation is required for migration ofDCs from peripheral sites, then it is diffi-cult to envisage how these cells wouldencounter naive T cells that do not haveaccess to normal, uninflamed tissues.Another possibility is that the phagocy-tosis of apoptotic cells by DCs in vivostimulates a form of ‘alternative activa-tion’ whereby the cells do not express co-stimulatory molecules but cannevertheless migrate centrally. One ques-tion that needs to be addressed is in factwhether DCs containing apoptotic con-tents can assume a regulatory functionand tolerize T-cell clones directly.

An additional possibility relates to theexistence of developmentally distinctsubsets of DCs, and suggests that‘myeloid’ DCs may be required for T cellactivation whereas ‘lymphoid’ DCs in-duce T-cell tolerance1,2, possibly relatedto their localization in different subcom-partments of ‘lymphoid’ tissues10.Whatever the case, the definition of DC-activating stimuli, preferably using in-creasingly powerful assays such asdifferential gene expression analysis, willbe essential for the development of newstrategies to selectively turn on or turnoff immune responses to our benefit.

1. Austyn, J.M. Dendritic cells. Curr. Opin. Hematol. 5,3–15 (1998).

2. Reis e Sousa, C., Sher A., & Kaye P. The role of den-dritic cells in the induction and regulation of im-munity to microbial infection. Curr. Opin. Immunol.11, 392–399 (1999).

3. Gallucci, S., Lolkema, M. & Matzinger, P. NaturalAdjuvants: Endogenous activators of dendriticcells. Nature Med. 5, 1249–1255 (1999).

4. Janeway, C.J. Approaching the asymptote?Evolution and revolution in immunology. Cold.Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

5. Matzinger, P. Tolerance, danger, and the extendedfamily. Annu. Rev. Immunol.12, 991–1045 (1994).

6. Rovere, P. et al. Bystander apoptosis triggers den-dritic cell maturation and antigen-presenting func-tion. J. Immunol. 161, 4467–4471 (1998).

7. Albert, M.L., Sauter, B. & Bhardwaj, N. Dendriticcells acquire antigen from apoptotic cells and in-duce class I-restricted CTLs. Nature 392, 86–89(1998).

8. Inaba, K. et al. Efficient presentation of phagocy-tosed cellular fragments on the major histocom-patibility complex class II products of dendriticcells. J. Exp. Med. 188, 2163–2173 (1998).

9. Heath, W.R., Kurts, C., Miller, J.F.A.P. & Carbone,F.R. Cross-tolerance: a pathway for inducing toler-ance to peripheral tissue antigens. J. Exp. Med. 187,1549–1553 (1998).

10. Fazekas de St Groth, B. The evolution of self-toler-ance: a new cell arises to meet the challenge ofself-reactivity. Immunol. Today 19, 448–454(1998).

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Email: jon.austyn@nds.ox.ac.uk

The great escape – AIDS viruses and immune controlMany studies have been designed to address the role of CTL immune escape in HIV-1 infection, but have not givenconclusive answers. Now, an elegant longitudinal analysis clearly demonstrates that progression to disease in SIV-

infected macaques is associated with evasion of the CTL response (pages 1270–1276).

PHILIP J.R. GOULDER1 &BRUCE D. WALKER2

EMERGING DATA INDICATE that cytotoxic Tlymphocytes (CTLs) are a potent

anti-viral defense mechanism inchronic viral infections. CTLs kill virus-infected cells through recognition ofviral peptides (epitopes) 8–11 aminoacids in length derived from proteolyti-

cally processed viral proteins that arepresented at the cell surface within theHLA class I binding cleft. However, CTLs

that are induced by human immunode-ficiency virus (HIV) infection and are soeffective in the short- and medium-termcontainment of virus1–2 are ultimatelyunable to control this infection. In thisissue of Nature Medicine, Evans et al3., re-

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