Protein kinase C-θ-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL

Santhakumar Manicassamy, Sonal Gupta, Zhaofeng Huang, Zuoming Sun

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Productive engagement of TCR results in delivering signals required for T cell proliferation as well as T cell survival. Blocking TCR-mediated survival signals, T cells undergo apoptosis instead of proliferation upon TCR stimulation. During the activation process, T cells produce IL-2, which acts as an extrinsic survival factor. In addition, TCR stimulation results in up-regulation of Bcl-xL to enhance T cell survival intrinsically. We show in this study that protein kinase C (PKC)-θ is required for enhancing the survival of activated CD4+ T cells by up-regulating Bcl-x L. In response to TCR stimulation, CD4+ PKC-θ-/- T cells failed to up-regulate Bcl-xL, and underwent accelerated apoptosis via a caspase- and mitochondria-dependent pathway. Similar to PKC-θ-deficient primary CD4+ T cells, small interfering RNA-mediated knockdown of PKC-θ in Jurkat cells also resulted in apoptosis upon TCR stimulation. Forced expression of Bcl-xL was sufficient to inhibit apoptosis observed in PKC-θ knockdown cells. Furthermore, ectopic expression of PKC-θ stimulated a reporter gene driven by a mouse Bcl-xL promoter. Whereas an inactive form of PKC-θ or knockdown of endogenous PKC-θ led to inhibition of Bcl-xL reporter. PKC-θ-mediated activation of Bcl-xL reporter was inhibited by dominant-negative IκB kinase β or dominant-negative AP-1. Thus, the PKC-θ-mediated signals may function not only in the initial activation of naive CD4+ T cells, but also in their survival during T cell activation by regulating Bcl-xL levels through NF-κB and AP-1 pathways.

Original languageEnglish (US)
Pages (from-to)6709-6716
Number of pages8
JournalJournal of Immunology
Volume176
Issue number11
DOIs
StatePublished - Jun 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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