The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation.
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.
Gelman
Andrew E
AE
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19010, USA.
LaRosa
David F
DF
Zhang
Jidong
J
Walsh
Patrick T
PT
Choi
Yongwon
Y
Sunyer
J Oriol
JO
Turka
Laurence A
LA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D018899:CpG Islands / Q000276:immunology*; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D007376:Interleukin-2; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019869:Phosphatidylinositol 3-Kinases