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A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells

Ma, Chao and Fan, Rong and Ahmad, Habib and Shi, Qihui and Comin-Anduix, Begonya and Chodon, Thinle and Koya, Richard C. and Liu, Chao-Chao and Kwong, Gabriel A. and Radu, Caius G. and Ribas, Antoni and Heath, James R. (2011) A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells. Nature Medicine, 17 (6). pp. 738-743. ISSN 1078-8956 . PMCID PMC3681612. http://resolver.caltech.edu/CaltechAUTHORS:20110621-120304768

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Abstract

Cellular immunity has an inherent high level of functional heterogeneity. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. We report a microfluidic platform designed for highly multiplexed (more than ten proteins), reliable, sample-efficient (~1 × 10^4 cells) and quantitative measurements of secreted proteins from single cells. We validated the platform by assessment of multiple inflammatory cytokines from lipopolysaccharide (LPS)-stimulated human macrophages and comparison to standard immunotechnologies. We applied the platform toward the ex vivo quantification of T cell polyfunctional diversity via the simultaneous measurement of a dozen effector molecules secreted from tumor antigen–specific cytotoxic T lymphocytes (CTLs) that were actively responding to tumor and compared against a cohort of healthy donor controls. We observed profound, yet focused, functional heterogeneity in active tumor antigen–specific CTLs, with the major functional phenotypes quantitatively identified. The platform represents a new and informative tool for immune monitoring and clinical assessment.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nm.2375DOIArticle
http://www.nature.com/nm/journal/v17/n6/full/nm.2375.htmlPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681612/PubMed CentralArticle
http://rdcu.be/g4fEPublisherFree ReadCube access
ORCID:
AuthorORCID
Heath, James R.0000-0001-5356-4385
Additional Information:© 2011 Nature Publishing Group, a division of Macmillan Publishers Limited. Received 10 October 2010; accepted 12 January 2011; published online 22 May 2011. We thank B. Marzolf at the Institute for Systems Biology for printing DNA-spotted arrays and the UCLA nanolab for photomask fabrication. We thank L. Yang, S. Wang, R. Diamond and H. Wu for valuable discussion. C.M. acknowledges the support of the Benjamin M. Rosen Fellowship. R.F. is supported by the US National Institutes of Health K99 Pathway to Independence Award (No. 1 K99 CA136759-01). This work was funded by the US National Cancer Institute Grant No. 5U54 CA119347 (J.R.H.), by the Ivy Foundation and the Jean Perkins Foundation (J.R.H.), by the California Institute for Regenerative Medicine New Faculty Award RN2-00902-1 (A.R.), by the Caltech/UCLA Joint Center for Translational Medicine (A.R. and J.R.H.) and the Melanoma Research Alliance (A.R. and J.R.H.). The UCLA Flow Cytometry Core Facility is supported by the US National Institutes of Health awards CA-16042 and AI-28697. Author Contributions: C.M. conducted T cell experiments and analyzed data. R.F. conducted macrophage experiments. C.M. and R.F. performed validation experiments and designed the chip. H.A. wrote Excel macros. Q.S., C.-C.L. and G.A.K. helped with experiments. B.C.-A., T.C. and R.C.K. collected T cell samples and conducted flow cytometry phenotyping experiments. C.M., R.F. and J.R.H. conceived of the experiments. C.M., R.F., C.G.R., A.R. and J.R.H. wrote the manuscript.
Group:Kavli Nanoscience Institute
Funders:
Funding AgencyGrant Number
Benjamin M. Rosen FellowshipUNSPECIFIED
NIH1 K99 CA136759-01
National Cancer Institute5U54 CA119347
Ivy FoundationUNSPECIFIED
Jean Perkins FoundationUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)RN2-00902-1
Caltech/UCLA Joint Center for Translational MedicineUNSPECIFIED
Melanoma Research AllianceUNSPECIFIED
NIHCA-16042
NIHAI-28697
PubMed Central ID:PMC3681612
Record Number:CaltechAUTHORS:20110621-120304768
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20110621-120304768
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:24159
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:21 Jun 2011 20:27
Last Modified:25 Apr 2017 04:49

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