N E W S A N D V I E W S

The T cell antigen receptor (TCR) is a mul-timeric complex composed of an antigen-

binding αβ heterodimer and a signal-transducing complex consisting of the CD3dimers (CD3γε and CD3δε) and a TCR ζhomodimer1. Down-regulation of the ζ chainprevents T cell activation and proliferation inresponse to cognate peptide bound to themajor histocompatibility complex of antigen-presenting cells (APCs). Several pathological

conditions, including chronic infections2,3,certain tumors4 and autoimmune diseases5

have been linked to a down-regulation of theζ chain (Fig. 1). In this issue of NatureImmunology, Baniyash and colleagues6 haveunlocked the molecular event leading to thisform of immune suppression.

Bronstein-Sitton et al. showed that ζ chaindown-regulation requires multiple exposuresof mice to heat-killed Porphyromonas gingi-valis as well as the production of interferon-γ(IFN-γ), a typical T helper type 1 (TH1)cytokine6. Down-regulation of the ζ chainwas mediated by lysosomal degradation,without involvement of the proteosome or gene transcription, and impaired theimmune response to influenza virus infection

(antigenically unrelated to P. gingivalis). T cellproliferation after stimulation by commonmitogens such as antibody to CD3 or con-canavalin A was also reduced. Uncoupling ofthe ζ chain from the TCR was associated witha mixed TH1-TH2 (or TH0) cytokine patternwith the production of both IFN-γ and inter-leukin 10 (IL-10). IFN-γ-deficient mice failedto down-regulate the ζ chain in the sameexperimental conditions, although IFN-γ wasnot the direct mediator of ζ down-regulation,as non-T cells present in the enlarged spleensof persistently stimulated mice induced ζchain down-regulation in the presence ofIFN-γ-neutralizing antibodies.

The innate and adaptive immune responsesare often divided on the basis of what type of

Guido Poli and Claudio Bordignon are at the San

Raffaele Scientific Institute and Vita-Salute San

Raffaele University, Milano 20132, Italy.

e-mail: claudio.bordignon@hsr.it

Unplugging the T cell receptorGuido Poli & Claudio Bordignon

Certain infectious diseases, autoimmune disorders and cancers are associated with T cell receptor ζ chain down-regulation. Interferon-γ production by T helper type 1 cells seems to be pivotal in this process.

NATURE IMMUNOLOGY VOLUME 4 NUMBER 10 OCTOBER 2003 943

al. raise the possibility that fusion betweenthe endoplasmic reticulum and phagosomesprovides the mechanism by which antigenscan be transferred from the phagosome tothe cytosol for antigen processing. In fact,Houde shows that one of the important pro-teins in this process, the SEC61 translocon, istransferred from the endoplasmic reticulumto the membrane of phagosomes2. SEC61 isnormally involved in the import of newlysynthesized proteins from ribosomes intothe endoplasmic reticulum. However, inways that are incompletely understood, thedirection of transport through SEC61 can bereversed10.

This reverse translocation of proteins outof the endoplasmic reticulum lumen may betightly linked to their degradation10. Inmany cases, transferred proteins must firstbe modified with the polypeptide ubiquitin,a process that is catalyzed by ubiquitin-conjugating enzymes associated with theouter membrane of the endoplasmic reticu-lum. Ubiquitination marks these proteinsfor rapid degradation by 26S proteasomes,and as part of this process, the proteasomes may help complete the extraction of theendoplasmic reticulum protein. Consistentwith this possibility, Houde finds that someof the antigen internalized into phagosomes

becomes polyubiquitinated and bound tophagosomes. Nevertheless, it remains to bedetermined whether SEC61, ubiquitin-conjugating enzymes and proteasomes areinvolved in transferring cross-presentedantigens out of phagosomes. Moreover, thefindings that enzymes transferred out ofphagosomes retain their activity (that is,their transfer is not linked to degradation)and that large dextran molecules (whichcannot be ubiquitinated and are unlikely tobe a substrate for Sec61) can also be trans-ferred to the cytosol4,8 may point to othertranslocation mechanisms.

The findings of Houde and Guermonprezmay provide insight into another mystery ofcross-presentation. Some cross-presentedpeptides are generated by proteases withinthe phagosome itself (the ‘vacuolar’ path-way). It has not been clear how class I mole-cules, which are not normally transportedinto endocytic compartments, acquire thesepeptides. One possibility was that the class Imolecules were internalized from the cellsurface, but most of these should alreadyhave bound peptides that would preventthem from acquiring new ones. The newfindings raise the possibility that endoplas-mic reticulum fusion provides both the peptide-empty class I molecules and the

peptide-loading molecule tapasin that canthen sample the peptides generated in thephagosome.

In conclusion, the studies by Houde et al.and Guermonprez show that phagosomesacquire several antigen-presentation compo-nents from the endoplasmic reticulum and cytosol that allow this organelle to gen-erate peptide-MHC molecules. The relativeimportance of this pathway versus others incross-priming now needs to be determined.These papers also raise the intriguing possibility that an endoplamic reticulum–donated protein-export pathway accountsfor the mysterious ability of phagosomes totransfer proteins into the cyotosol for degra-dation and cross-priming; however, thisremains to be directly tested.

1. Heath, W.R. & Carbone, F.R. Annu. Rev. Immunol.19, 47–64 (2001).

2. Houde, M. et al. Nature online publication, 24September 2003 (doi:10.1038/nature01912).

3. Guermonprez, P. et al. Nature online publication, 24September 2003 (doi:10.1038/nature01911).

4. Rock, K.L. Immunol. Today 17, 131–7 (1996).5. Sigal, L.J., Crotty, S., Andino, R. & Rock, K.L.

Nature 398, 77–80 (1999).6. Gagnon, E. et al. Cell 110, 119–31 (2002).7. York, I.A. et al. Immunity 18, 429–40 (2003).8. Watts, C. Annu. Rev. Immunol. 15, 821–50 (1997).9. Rock, K.L. et al. Cell 78, 761–771 (1994).10. Tsai, B., Ye, Y. & Rapoport, T.A. Nat. Rev. Mol. Cell.

Biol. 3, 246–55 (2002).

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N E W S A N D V I E W S

receptors are involved in pathogen recogni-tion. However, the finding that IFN-γproduc-tion induced ζ chain down-regulationindicates this distinction is not so clear-cut.The finding that IFN-γ production by APCsimpairs T cell function through production ofreactive oxygen intermediates7 would com-plete the circle between the innate and adap-tive immune response in the Bronstein-Sittonmodel (Fig. 1). Indeed, the non-T cells thatmediate ζ chain down-regulation could perhaps produce reactive oxygen intermedi-ates, but it remains to be seen whether these

intermediates can actually induce ζ chaindown-regulation.

Several considerations arise from this ele-gant study. It sheds new light on the closeinteraction between the different arms of theimmune system. Innate and specific immu-nity are commonly regulated, and it is becom-ing increasingly apparent that the distinctionconventionally made demonstrates our lim-ited capacity to fully understand how theimmune system works rather than its actualfunctioning. Moreover, although the func-tional defect described by the authors did notcause persistent ζ chain down-regulation atthe protein or mRNA level, it was profoundenough to cause a generalized deficiency inresponse to an unrelated pathogen, in thiscase influenza virus. Furthermore, the ideathat IFN-γ, directly or indirectly, down-regulates cell function is relatively counterin-tuitive. IFN-γ is one of the most potent activa-tors of macrophage function and is a keydeterminant of phagocyte-dependent TH1responses. As the authors point out, non-Tcells, including natural killer cells8 andmacrophages7,9, can produce IFN-γ. Thisstudy6 suggests that recruitment of these cellsto secondary lymphoid organs, such as thespleen, which are distant from the site of anti-gen inoculation, may induce ζ chain down-regulation in a substantial fraction of T cellsthrough a bystander effect. IFN-γ would be acrucial trigger, but it could be dispensable forthe ‘execution’ phase that functionallyimpairs T cells.

The identification of the chemotactic sig-nals leading to accumulation of the non-Tregulatory cells and whether these signals arecontrolled by IFN-γ or other TH1-relatedcytokines remains to be seen. Regulatory cellsare usually described as CD4+CD25+CD69– Tlymphocytes that inhibit the activation andproliferation of CD4+CD25– T cells by cell-cell contact10,11. It is unclear whether thenon-T cells exerting down-regulatory effectsdescribed in this study use a similar cell-to-cell mechanism or act by release of cytokinesand other soluble mediators.

The study by Baniyash and colleagues6 pro-vides a unifying view of the molecular mecha-nism leading to ζ chain down-regulation,opening new opportunities for immunologicreconstitution. The profound ζ chain down-regulation that mainly affects CD8+ T cellsdescribed in individuals infected with humanimmunodeficiency virus can be promptly

rescued by in vitro incubation of the cells withIL-2 (ref. 2). Because intermittent adminis-tration of IL-2 is now being pursued as apotential form of immunological therapy inhuman immunodeficiency virus disease12

and is already used to treat certain tumors,the ability of IL-2 to revert ζ chain down-regulation may be important in its provenability to reconstitute the immune system. Atpresent, it is unclear whether IL-2 or othercytokines can restore ζ chain expression inthe model used by Baniyash and colleagues.For example, IL-2 could potentially influencethe activation or recruitment of non-T regu-latory cells.

This study also suggests that genetic engi-neering of T lymphocytes to constitutivelyexpress the ζ chain may generate effector cellscapable of effectively controlling pathogensthat escape the immune system by inducing ζchain down-regulation13. This idea is nowbeing tested at the clinical level in patientsinfected with human immunodeficiencyvirus. Because tumors may also escape adap-tive immunosurveillance through TCR ζchain down-regulation, T cells geneticallyengineered to constitutively express the ζchain should also be considered for immuno-therapy of certain tumors. In conclusion, theidentification of the crucial molecular eventresponsible for this transient, but profoundform of immunodeficiency opens new per-spectives not only for understanding thedynamics of T cell immune responses toinfectious pathogens but also for designingnew therapeutic strategies against certaintumors and autoimmune diseases.

1. Kane, L.P., Lin, J. & Weiss, A. Curr. Opin. Immunol.12, 242–249 (2000).

2. Trimble, L.A. & Lieberman, J. Blood 91, 585–594(1998).

3. Zea, A.H. et al. Infect. Immun. 66, 499–504 (1998).4. Finke, J.H. et al. Cancer Res. 53, 5613–5616 (1993).5. Maurice, M.M. et al. J. Immunol. 159, 2973–2978

(1997).6. Bronstein-Sitton, N. et al. Nat. Immunol. 4, 957–964

(2003).7. Frucht, D.M. et al. Trends Immunol. 22, 556–560

(2001).8. Allavena, P. et al. Cancer Immunol. Immunother. 19,

121–126 (1985).9. Gessani, S. & Belardelli, F. Cytokine Growth Factor

Rev. 9, 117–123 (1998).10. Roncarolo, M.G., Levings, M.K. & Traversari, C.

J. Exp. Med. 193, F5–9 (2001).11. Shevach, E.M. Nat. Rev. Immunol. 2, 389–400 (2002).12. Paredes, R., Lopez Benaldo de Quiros, J.C.,

Fernandez-Cruz, E., Clotet, B. & Lane, H.C. AIDS Rev.4, 36–40 (2002).

13. Walker, R.E. et al. Blood 96, 467–474 (2000).

944 VOLUME 4 NUMBER 10 OCTOBER 2003 NATURE IMMUNOLOGY

Figure 1 Reversible impairment of T cell functionthrough down-regulation of the TCR ζ chain.Unrelated diseases induce a defective T cellresponse by uncoupling the ζ-transducing chainfrom the TCR. Bronstein-Sitton and colleaguesdemonstrate that this phenomenon depends onlysosomal but not proteosomal degradation of theprotein without interference at the transcriptionallevel. Antigen persistence leading to IFN-γproduction seems crucial for inducing such adown-regulation of ζ. The authors propose that aregulatory population of cells not belonging to theT cell lineage is the ultimate effector of thisreversible form of immunodeficiency. Ag, antigen;MHC, major histocompatibility complex; dashedline, hypothetical mechanism.

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