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PNAS 105 (22): 7791-7796

Copyright © 2008 by the National Academy of Sciences.

From the Cover


PHYSICAL SCIENCES / BIOLOGICAL SCIENCES / ENGINEERING / IMMUNOLOGY

Micropatterning of costimulatory ligands enhances CD4+ T cell function

Keyue Shen*, V. Kaye Thomas{dagger}, Michael L. Dustin{dagger}, and Lance C. Kam*,{ddagger}

*Department of Biomedical Engineering, Columbia University, New York, NY 10027; and {dagger}Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016

Edited by Arthur Weiss, University of California School of Medicine, San Francisco, CA, and approved March 19, 2008

Received for publication October 30, 2007.

Abstract: Spatial organization of signaling complexes is a defining characteristic of the immunological synapse (IS), but its impact on cell communication is unclear. In T cell–APC pairs, more IL-2 is produced when CD28 clusters are segregated from central supramolecular activation cluster (cSMAC)-localized CD3 and into the IS periphery. However, it is not clear in these cellular experiments whether the increased IL-2 is driven by the pattern itself or by upstream events that precipitate the patterns. In this article, we recapitulate key features of physiological synapses using planar costimulation arrays containing antibodies against CD3 and CD28, surrounded by ICAM-1, created by combining multiple rounds of microcontact printing on a single surface. Naïve T cells traverse these arrays, stopping at features of anti-CD3 antibodies and forming a stable synapse. We directly demonstrate that presenting anti-CD28 in the cell periphery, surrounding an anti-CD3 feature, enhances IL-2 secretion by naïve CD4+ T cells compared with having these signals combined in the center of the IS. This increased cytokine production correlates with NF-{kappa}B translocation and requires PKB/Akt signaling. The ability to arbitrarily and independently control the locations of anti-CD3 and anti-CD28 offered the opportunity to examine patterns not precisely attainable in cell–cell interfaces. With these patterns, we show that the peripheral presentation of CD28 has a larger impact on IL-2 secretion than CD3 colocalization/segregation.

Key Words: costimulation • immunology • naïve T cells • microarrays


Author contributions: K.S., M.L.D., and L.C.K. designed research; K.S. and V.K.T. performed research; K.S., M.L.D., and L.C.K. analyzed data; and K.S., M.L.D., and L.C.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0710295105/DCSupplemental.

{ddagger}To whom correspondence should be addressed. E-mail: lk2141{at}columbia.edu

© 2008 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cross Talk between CD3 and CD28 Is Spatially Modulated by Protein Lateral Mobility.
K. T. Bashour, J. Tsai, K. Shen, J.-H. Lee, E. Sun, M. C. Milone, M. L. Dustin, and L. C. Kam (2014)
Mol. Cell. Biol. 34, 955-964
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CD28 and CD3 have complementary roles in T-cell traction forces.
K. T. Bashour, A. Gondarenko, H. Chen, K. Shen, X. Liu, M. Huse, J. C. Hone, and L. C. Kam (2014)
PNAS 111, 2241-2246
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Spatial organization of transmembrane receptor signalling.
I. Bethani, S. S. Skanland, I. Dikic, and A. Acker-Palmer (2010)
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Adoptive T-cell therapy for malignant disorders.
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T Cell-Dendritic Cell Immunological Synapses Contain TCR-dependent CD28-CD80 Clusters That Recruit Protein Kinase C{theta}.
S.-Y. Tseng, J. C. Waite, M. Liu, S. Vardhana, and M. L. Dustin (2008)
J. Immunol. 181, 4852-4863
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