Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms

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• 作者：Belén Blanco ; Ma Carmen Herrero-Sánchez…
• 关键词：T lymphocyte ; PI3K inhibitor ; p110 isoform
• 刊名：Immunologic Research
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：62
• 期：2
• 页码：175-188
• 全文大小：1,990 KB
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• 作者单位：Belén Blanco (1)
  Ma Carmen Herrero-Sánchez (1)
  Concepción Rodríguez-Serrano (1)
  Mercedes Sánchez-Barba (2)
  Ma Consuelo del Ca?izo (1)
  
  1. Servicio de Hematología, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente, s/n., 37007, Salamanca, Spain
  2. Departamento de Estadística, Universidad de Salamanca, Salamanca, Spain
  
• 刊物主题：Allergology; Immunology; Medicine/Public Health, general; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-0755

文摘

PI3K inhibitors have emerged as potential therapeutic tools for a variety of diseases, and thus, a vast array of compounds with specificity for different PI3K isoforms is being developed. Gaining knowledge about the contribution of the different isoforms to PI3K function will allow selecting the most appropriate inhibitor for each pathology. In this study, we have addressed the effect of PI3K inhibitors with specificity for different class I PI3K isoforms on primary human T cell activation. In particular, we have analyzed proliferation, expression of activation and differentiation markers, apoptosis induction, cytokine secretion and Akt phosphorylation in T cells stimulated in vitro with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either one of these compounds: p110β-specific inhibitor TGX-221, p110δ-specific inhibitor IC-87114, p110γ inhibitor AS-242525 or pan-class I PI3K inhibitor BKM120. Inhibition of any of the isoforms led to an impairment of T cell activation, mainly of cytokine secretion and granzyme B expression. However, only complete blockade of class I PI3K activity with the pan-class I inhibitor effectively abrogated T cell proliferation. These results indicate that these three p110 isoforms (β, δ and γ) take part in T cell activation, but all of them are dispensable for T cell proliferation.