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Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278)

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Abstract

To better understand T lymphocyte costimulation by inducible costimulator (ICOS; H4; CD278), we analyzed proteins binding to ICOS peptides phosphorylated at the Y191MFM motif. Phosphorylated ICOS binds class IA phosphatidyl inositol 3-kinase (PI3-K) p85α, p50-55α and p85β regulatory subunits and p110α, p110δ and p110β catalytic subunits. Intriguingly, T cells expressed high levels of both p110α or p110δ catalytic subunits, yet ICOS peptides, cell surface ICOS or PI3-kinase class IA regulatory subunits preferentially coprecipitated p110α catalytic subunits. Silencing p110α or p110δ partially inhibited Akt/PKB activation induced by anti-CD3 plus anti-ICOS antibodies. However, silencing p110α enhanced and silencing p110δ inhibited Erk activation. Both p110α- and p110δ-specific inhibitors blocked cytokine secretion induced by TCR/CD3 activation with or without ICOS costimulus, but only p110α inhibitors blocked ICOS-induced cell elongation. Thus, p110α and p110δ are essential to optimal T cell activation, but their abundance and activity differentially tune up distinct ICOS signaling pathways.

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Acknowledgments

The skillful technical assistance of Maria Luisa del Pozo and Marta Blanco-Berrocal is gratefully acknowledged. Y.Y.A. is the recipient of a Predoctoral Fellowship of the “Junta de Ampliación de Estudios” (JAE) Program (C.S.I.C., Ministerio de Ciencia e Innovación, Spain). P.P. is a Tenured Sciencist of C.S.I.C. at the Centro Nacional de Microbiología, I.S.: Carlos III. This work was supported by grants PI070620 and PI070484 (Fondo de Investigación Sanitaria, Ministerio de Ciencia e Innovación, Spain) and by AIRC (Milan) (to U.D.).

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The authors declare no financial conflict of interest.

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Authors and Affiliations

  1. Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, 28040, Madrid, Spain

    Yenny Y. Acosta, Maria Paz Zafra, Ilaria Seren Bernardone & Jose M. Rojo

  2. Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220, Madrid, Spain

    Gloria Ojeda & Pilar Portolés

  3. Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), “A. Avogadro” University of Eastern Piedmont, 28100, Novara, Italy

    Ilaria Seren Bernardone & Umberto Dianzani

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  1. Yenny Y. Acosta
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Correspondence to Jose M. Rojo.

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Y. Y. Acosta and M. P. Zafra contributed equally to this work.

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Acosta, Y.Y., Zafra, M.P., Ojeda, G. et al. Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278). Cell. Mol. Life Sci. 68, 3065–3079 (2011). https://doi.org/10.1007/s00018-010-0606-1

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