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Self and Viral Antigens That Augment the T Cell Response

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Self and Viral Antigens That Augment the T Cell Response Quantum dot/peptide-MHC biosensors reveal strong CD8-dependent cooperation between self and viral antigens that augment the T cell response Nadia Anikeeva, Tatiana Lebedeva, Aaron R. Clapp, Ellen R. Goldman, Michael L. Dustin, Hedi Mattoussi, and Yuri Sykulev PNAS 2006;103;16846-16851; originally published online Oct 31, 2006; doi:10.1073/pnas.0607771103 This information is current as of February 2007. Online Information High-resolution figures, a citation map, links to PubMed and Google Scholar, & Services etc., can be found at: www.pnas.org/cgi/content/full/103/45/16846 Supplementary Material Supplementary material can be found at: www.pnas.org/cgi/content/full/0607771103/DC1 References This article cites 37 articles, 12 of which you can access for free at: www.pnas.org/cgi/content/full/103/45/16846#BIBL This article has been cited by other articles: www.pnas.org/cgi/content/full/103/45/16846#otherarticles E-mail Alerts Receive free email alerts when new articles cite this article - sign up in the box at the top right corner of the article or click here. Rights & Permissions To reproduce this article in part (figures, tables) or in entirety, see: www.pnas.org/misc/rightperm.shtml Reprints To order reprints, see: www.pnas.org/misc/reprints.shtml Notes: Quantum dot͞peptide-MHC biosensors reveal strong CD8-dependent cooperation between self and viral antigens that augment the T cell response Nadia Anikeeva*, Tatiana Lebedeva*, Aaron R. Clapp†, Ellen R. Goldman†, Michael L. Dustin‡, Hedi Mattoussi†§, and Yuri Sykulev*§ *Department of Microbiology and Immunology and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107; †U.S. Naval Research Laboratory, Optical Sciences Division, and Center for Bio͞Molecular Science and Engineering, Washington, DC 20375; and ‡Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016 Communicated by Herman N. Eisen, Massachusetts Institute of Technology, Cambridge, MA, September 5, 2006 (received for review July 26, 2006) Cytotoxic T lymphocytes (CTL) can respond to a few viral peptide- In this report, we use self-assembled QD͞pMHC-I conjugates (in MHC-I (pMHC-I) complexes among a myriad of virus-unrelated which the MHC-I protein is HLA-A2) to evaluate mechanisms of endogenous self pMHC-I complexes displayed on virus-infected antigen recognition by TCR on live CD8ϩ T cells. These QD͞ cells. To elucidate the molecular recognition events on live CTL, we pHLA-A2 conjugates offer (i) a unique architecture with coherent have utilized a self-assembled biosensor composed of semicon- orientation and spacing between proteins on the nanocrystal and ductor nanocrystals, quantum dots, carrying a controlled number (ii) control over the number of pHLA-A2 complexes immobilized of virus-derived (cognate) and other (noncognate) pMHC-I com- on each QD. The binding of QDs carrying a predetermined number plexes and examined their recognition by antigen-specific T cell of cognate and noncognate pHLA-A2 complexes to live T cells receptor (TCR) on anti-virus CD8؉ T cells. The unique architecture shows that strong multivalent interactions between CD8 and of nanoscale quantum dot͞pMHC-I conjugates revealed that un- MHC-I dominate the stability of TCR͞pMHC-I͞CD8 complexes expectedly strong multivalent CD8–MHC-I interactions underlie and underlie striking noncognate pMHC-I cooperation with cog- the cooperative contribution of noncognate pMHC-I to the recog- nate pMHC-I that enhances T cell responses. nition of cognate pMHC-I by TCR to augment T cell responses. The On the basis of these and other findings we suggest that strong, cooperative, CD8-dependent spread of signal from a few produc- TCR-independent CD8–MHC-I interactions precede recognition tively engaged TCR to many other TCR can explain the remarkable of pMHC-I by TCR and facilitate rapid signal spreading from a few ability of CTL to respond to virus-infected cells that present few agonist-bound TCR to many other receptors within TCR clusters. cognate pMHC-I complexes. This cooperative mechanism explains the highly sensitive response of CTL, which can respond to as few as perhaps a single cognate CD8 coreceptor ͉ peptide-MHC clustering ͉ sensitivity of T cell pMHC-I on a target cell (10, 11). responses ͉ antivirus immunity Results The QD͞pMHC Biosensor. Nonradiative resonance energy transfer ecognition of peptide-MHC (pMHC) complexes presented on between a central QD and proximal dyes attached to the HLA-A2 Rthe surface of infected cells by T cell receptors (TCR) initiates protein was used to test conjugate formation and to determine the the T cell response against these cells. While TCR specifically ratio of QD to pHLA-A2. Fig. 1a shows that changes in the recognizes peptide and polymorphic helices of MHC class I and deconvoluted photoluminescence (PL) signal of the solutions con- class II proteins (1), the nonpolymorphic domain of these MHC taining QD donors emitting at 530 nm and pHLA-A2 labeled with proteins also interacts with the CD8 and CD4 coreceptors that Alexa Fluor 555 acceptors are ratio dependent. These changes ϩ ϩ mark distinct populations of T lymphocytes, i.e., CD8 and CD4 constitute a reliable indicator of protein immobilization on the QDs T cells. The MHC–coreceptor interactions occur regardless of the (5). Fig. 1b depicts the experimental values of the integrated PL nature of MHC-bound peptide (2). Because MHC-I is expressed on signal as a function of dye-to-QD ratio. Because the dye was bound ϩ every nucleated cell, CD8 T cells (also known as cytotoxic T randomly to ␧-amino groups on the protein surface, the data were lymphocytes or CTL), can recognize and, if necessary, respond to simulated by using a variable donor–acceptor separation distances virtually any infected cell in the body, and thus play a key role in (with a normal distribution function). The best fit of the experi- anti-virus immunity. mental data to theoretical curves was based on Fo¨rster formalism Unraveling molecular recognition events as they occur at the cell and was achieved by using a range of separation distances between membrane of T cells is essential for understanding mechanisms donor and acceptor centered at 75 Å and a width of 40 Å. These responsible for the unique sensitivity and selectivity of the T cell values are consistent with the dimensions of the inorganic QD response. Soluble MHC proteins and their oligomers (3) have been (core-shell) and the HLA-A2 protein molecule attached through extensively used for this purpose. However, the majority of these the C terminus to the QD surface. The dependence of the PL oligomers, MHC tetramers in particular, may not mimic the ori- signals on the ratio of labeled protein to QD also indicates that entation and the typical distances between MHC monomers in their natural environment, and these limitations may influence the results of experiments in which these oligomers are used to explore Author contributions: N.A., A.R.C., M.L.D., H.M., and Y.S. designed research; N.A., T.L., TCR-mediated molecular events on the T cell surface. Indeed, the A.R.C., and E.R.G. performed research; H.M. contributed new reagents͞analytic tools; N.A., T.L., A.R.C., E.R.G., H.M., and Y.S. analyzed data; and N.A., T.L., A.R.C., M.L.D., H.M., and Y.S. architecture of a multivalent ligand that binds to clustered receptors wrote the paper. can strongly influence the ligand’s biological activity (4). The authors declare no conflict of interest. Luminescent semiconductor nanocrystals (quantum dots, QDs) Abbreviations: CTL, cytotoxic T lymphocyte(s); MFI, mean fluorescence intensity; PL, pho- provide excellent nanoscaffolds to array several receptor molecules toluminescence; pMHC, peptide-MHC; QD, quantum dot(s); TCR, T cell receptor(s). on their surfaces by metal-affinity-driven self-assembly, providing §To whom correspondence may be addressed. E-mail: [email protected] or hedimat@ aggregate-free solutions of QD conjugates that specifically recog- ccs.nrl.navy.mil. nize their respective ligands (5–9). © 2006 by The National Academy of Sciences of the USA 16846–16851 ͉ PNAS ͉ November 7, 2006 ͉ vol. 103 ͉ no. 45 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0607771103 Fig. 1. Formation of functional QD͞pHLA-A2 conjugates. (a) Deconvoluted photoluminescence (PL) spectra of QD and Alexa Fluor 555 (AF555)-labeled pHLA-A2 for different dye-to-protein ratios are shown. a.u., atomic units. (b) Changes of the fluorescence intensity versus the dye-to-QD ratio show that up to 12 pHLA-A2 complexes can be attached to each QD. FRET, Fo¨ rster resonance energy transfer. (c) Immobilized D3 TCR specifically recognize cognate (QD͞ SL9-HLA-A2) but not noncognate (QD͞IV9-HLA-A2) conjugates at 150 nM. Data shown are representative of four independent experiments. (d) Sche- matic drawing of QD͞SL9-HLA-A2 conjugate bound to TCR immobilized on a plastic surface. Fig. 2. Binding of QD͞pHLA-A2 conjugates to the surface of live CTL. (a) Although cognate QD͞GL9-HLA-A2 conjugate binds specifically to CER43 CTL, noncognate QD͞IV9-HLA-A2 conjugate shows high TCR-independent binding saturation of the surface with protein occurs at protein-to-QD to the CTL. QD concentration was 1 ␮M; the binding was performed for 30 min at 4°C. (b) Schematic drawing of QD͞HLA-A2 and peptide complexed with a ratios slightly exceeding 12, a value consistent with a maximum TCR bound to the membrane of a CD8ϩ cell. (c and d) Binding of cognate allowed by steric limitations of the protein packing around a (QD͞GL9-HLA-A2) (c) but not noncognate (QD͞IV9-HLA-A2) (d) conjugates to nanocrystal (7). CER43 CTL leads to internalization of the QD conjugates.
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