ICOS ligation recruits the p50alpha PI3K regulatory subunit to the immunological synapse.
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 p85alpha 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 p50alpha, one of the regulatory subunits of class IA PI3Ks. Using different T-APC cell conjugate systems, we report that p50alpha 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 p50alpha 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 p50alpha at the synapse of T cell/APC conjugates. In association with the p110 catalytic subunit, p50alpha is known to carry a stronger lipid kinase activity compared with p85alpha. Accordingly, we observed that ICOS engagement results in a stronger activation of PI3K. Together, these findings provide evidence that p50alpha 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.
Fos
Camille
C
Institut National de la Santé et de la Recherche Médicale, Unité 891, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Salles
Audrey
A
Lang
Valérie
V
Carrette
Florent
F
Audebert
Stéphane
S
Pastor
Sonia
S
Ghiotto
Marguerite
M
Olive
Daniel
D
Bismuth
Georges
G
Nunès
Jacques A
JA
D020816:Amino Acid Motifs; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D060889:Inducible T-Cell Co-Stimulator Protein; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; C556692:ICOS protein, human