ICOS ligation recruits the p50alpha PI3K regulatory subunit to the immunological synapse

J Immunol. 2008 Aug 1;181(3):1969-77. doi: 10.4049/jimmunol.181.3.1969.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • Antigens, Differentiation, T-Lymphocyte / metabolism*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cricetinae
  • Humans
  • Inducible T-Cell Co-Stimulator Protein
  • Lymphocyte Activation / immunology
  • Lymphocytes / enzymology
  • Lymphocytes / immunology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / immunology


  • Antigens, Differentiation, T-Lymphocyte
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Protein Subunits
  • Proto-Oncogene Proteins c-akt