| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PI3K Regulatory Subunit to the Immunological Synapse1
,
,
,¶,¶,,,,,¶,
* Institut National de la Santé et de la Recherche Médicale, Unité 891, Centre de Recherche en Cancérologie de Marseille, Marseille, France;
Institut Paoli-Calmettes, Marseille, France;
Université de la Méditerranée, Marseille, France;
Institut Cochin, Centre National de la Recherche Scientifique (UMR 8104), Université Paris Descartes, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France; and
¶ Institut National de la Santé et de la Recherche Médicale, Unité 567, Paris, France
ICOS ligation in concert with TCR stimulation results in strong PI3K activation in T lymphocytes. The ICOS cytoplasmic tail contains an YMFM motif that binds the p85
subunit of class IA PI3K, similar to the YMNM motif of CD28, suggesting a redundant function of the two receptors in PI3K signaling. However, ICOS costimulation shows greater PI3K activity than CD28 in T cells. We show in this report that ICOS expression in activated T cells triggers the participation of p50, one of the regulatory subunits of class IA PI3Ks. Using different T-APC cell conjugate systems, we report that p50 accumulates at the immunological synapse in activated but not in resting T cells. Our results demonstrate that ICOS membrane expression is involved in this process and that p50 plasma membrane accumulation requires a functional YMFM Src homology 2 domain-binding motif in ICOS. We also show that ICOS triggering with its ligand, ICOSL, induces the recruitment of p50 at the synapse of T cell/APC conjugates. In association with the p110 catalytic subunit, p50 is known to carry a stronger lipid kinase activity compared with p85. Accordingly, we observed that ICOS engagement results in a stronger activation of PI3K. Together, these findings provide evidence that p50 is likely a determining factor in ICOS-mediated PI3K activity in T cells. These results also suggest that a differential recruitment and activity of class IA PI3K subunits represents a novel mechanism in the control of PI3K signaling by costimulatory molecules.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Institut National de la Santé et de la Recherche Médicale and from Institut National du Cancer (PL-06026). C.F. was supported by fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche and from the Fondation pour la Recherche Médicale.
2 Current address: Mass Spectrometry and Proteomics Platform, Institut de Cancérologie et d’Immunologie de Marseille (IFR137) Centre de Recherche en Cancérologio de Marseille, Unité Mixte de Recherche 891 Inserm-Institut Paoli-Calmettes, 13009 Marseille, France.
3 Address correspondence and reprint requests to Dr. Jacques A. Nunès, Centre de Recherche en Cancérologie de Marseille, 27 Boulevard Lei Roure, 13009 Marseille, France. E-mail address: jacques.nunes{at}inserm.fr
4 Abbreviations used in this paper: SH2, Src homology 2 domain; IS, immunological synapse; DC, dendritic cell; L-LICOS, L cells stably expressing the ICOS-L protein; GSK-3, glycogen synthase kinase-3.
This article has been cited by other articles:
|
|
 |
|
  J. L. Franko and A. D. Levine Antigen-independent adhesion and cell spreading by inducible costimulator engagement inhibits T cell migration in a PI-3K-dependent manner J. Leukoc. Biol., March 1, 2009; 85(3): 526 - 538. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
