HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sanchez-Lockhart, M. Articles by Miller, J. Search for Related Content PubMed PubMed Citation Articles by Sanchez-Lockhart, M. Articles by Miller, J.

Engagement of CD28 Outside of the Immunological Synapse Results in Up-Regulation of IL-2 mRNA Stability but Not IL-2 Transcription¹

David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences and the Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642

During T cell activation by APC, CD28 is colocalized with TCR in the central supramolecular activation cluster (cSMAC) region of the immunological synapse. CD28 signaling through PI3K results in the recruitment of protein kinase C (PKC) to the cSMAC, activation of NF-B, and induction of IL-2 transcription. These results suggest that localized engagement of CD28 within the cSMAC may be required for CD28 activation and/or signal integration with TCR signals. To test this model we have examined the mechanism of CD28-mediated induction of IL-2 secretion when CD28 is engaged outside of the immunological synapse. CD4 T cells were stimulated with Ag presented by B7-negative APC and CD28 costimulation was provided in trans by anti-CD28-coated beads or by class II-negative, B7-positive cells. We show that induction of IL-2 secretion under these conditions did not require expression of PKC and did not induce NF-B activation or IL-2 transcription. In contrast, CD28 costimulation in trans did induce IL-2 mRNA stability, accounting for the up-regulation of IL-2 secretion. These data indicate that the ability of CD28 to up-regulate IL-2 transcription requires colocalization of TCR and CD28 at the plasma membrane, possibly within the cSMAC of the immunological synapse. In contrast, the ability of CD28 to promote IL-2 mRNA stability can be transduced from a distal site from the TCR, suggesting that signal integration occurs downstream from the plasma membrane. These data support the potential role of trans costimulation in tumor and allograft rejection, but limit the potential functional impact that trans costimulation may have on T cell activation.

This article has been cited by other articles:

				M. Sanchez-Lockhart, B. Graf, and J. Miller Signals and Sequences That Control CD28 Localization to the Central Region of the Immunological Synapse J. Immunol., December 1, 2008; 181(11): 7639 - 7648. [Abstract] [Full Text] [PDF]

				K. Shen, V. K. Thomas, M. L. Dustin, and L. C. Kam From the Cover: Micropatterning of costimulatory ligands enhances CD4+ T cell function PNAS, June 3, 2008; 105(22): 7791 - 7796. [Abstract] [Full Text] [PDF]

				B. Graf, T. Bushnell, and J. Miller LFA-1-Mediated T Cell Costimulation through Increased Localization of TCR/Class II Complexes to the Central Supramolecular Activation Cluster and Exclusion of CD45 from the Immunological Synapse J. Immunol., August 1, 2007; 179(3): 1616 - 1624. [Abstract] [Full Text] [PDF]

				K. S. A. Khabar Rapid transit in the immune cells: the role of mRNA turnover regulation J. Leukoc. Biol., June 1, 2007; 81(6): 1335 - 1344. [Abstract] [Full Text] [PDF]