The Adaptor Molecule MyD88 Activates PI-3 Kinase Signaling in CD4+ T Cells and Enables CpG Oligodeoxynucleotide-Mediated Costimulation

  • Gelman A
  • LaRosa D
  • Zhang J
 et al. 
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Abstract

While T cells respond directly to toll-like receptor (TLR) agonists, TLR-signaling pathways in T cells are poorly characterized. Here we demonstrate in CD4+T cells that CpG DNA directly enhances proliferation, prevents anergy, and augments humoral responses to a T cell-dependent antigen by a Myeloid differentiation primary-response protein 88 (MyD88) and Phosphatidylinositol 3-kinase (PI-3 kinase)-dependent pathway. PI-3 kinase activation required a putative Src-homology domain (SH2) binding motif in the MyD88 Toll-Like or IL-1 Receptor (TIR) domain. Reconstitution of MyD88-deficient primary T cells with a MyD88 transgene mutated in this motif abrogated association of PI-3 kinase with MyD88, phosphorylation of protein kinase B (Akt) and Glycogen Synthetase Kinase-3 (GSK-3), and interleukin-2 (IL-2) production. The MyD88 death domain, on the other hand, was required for NF-kB activation and survival. These studies identify a MyD88-dependent PI-3 kinase-signaling pathway in T cells that differentiates CpG DNA-mediated proliferation from survival and is required for an in vivo T cell-dependent immune response. © 2006 Elsevier Inc. All rights reserved.

Author-supplied keywords

  • MOLIMMUNO
  • SIGNALING

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Authors

  • Andrew E. Gelman

  • David F. LaRosa

  • Jidong Zhang

  • Patrick T. Walsh

  • Yongwon Choi

  • J.  Oriol Sunyer

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