The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation

被引:169
作者
Gelman, Andrew E.
LaRosa, David F.
Zhang, Jidong
Walsh, Patrick T.
Choi, Yongwon
Sunyer, J. Oriol
Turka, Laurence A. [1 ]
机构
[1] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19010 USA
[2] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19010 USA
[3] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA
关键词
D O I
10.1016/j.immuni.2006.08.023
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:783 / 793
页数:11
相关论文
共 43 条
[11]   Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse [J].
Costello, PS ;
Gallagher, M ;
Cantrell, DA .
NATURE IMMUNOLOGY, 2002, 3 (11) :1082-1089
[12]   NF-κB activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-θ [J].
Coudronniere, N ;
Villalba, M ;
Englund, N ;
Altman, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (07) :3394-3399
[13]   Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells [J].
Crellin, NK ;
Garcia, RV ;
Hadisfar, O ;
Allan, SE ;
Steiner, TS ;
Levings, MK .
JOURNAL OF IMMUNOLOGY, 2005, 175 (12) :8051-8059
[14]   DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA [J].
Dragoi, AM ;
Fu, XY ;
Ivanov, S ;
Zhang, P ;
Sheng, LB ;
Wu, DQ ;
Li, GC ;
Chu, WM .
EMBO JOURNAL, 2005, 24 (04) :779-789
[15]   Adaptor usage and Toll-like receptor signaling specificity [J].
Dunne, A ;
O'Neill, LAJ .
FEBS LETTERS, 2005, 579 (15) :3330-3335
[16]   Evidence for phosphatidylinositol 3-kinase-dependent T cell antigen receptor (TCR) signal transduction [J].
Exley, M ;
Varticovski, L .
MOLECULAR IMMUNOLOGY, 1997, 34 (03) :221-226
[17]  
Ferguson SE, 1996, J IMMUNOL, V156, P4576
[18]   PI3K-mediated negative feedback regulation of IL-12 production in DCs [J].
Fukao, T ;
Tanabe, M ;
Terauchi, Y ;
Ota, T ;
Matsuda, S ;
Asano, T ;
Kadowaki, T ;
Takeuchi, T ;
Koyasu, S .
NATURE IMMUNOLOGY, 2002, 3 (09) :875-881
[19]   Toll-like receptor ligands directly promote activated CD4+ T cell survival [J].
Gelman, AE ;
Zhang, JD ;
Choi, Y ;
Turka, LA .
JOURNAL OF IMMUNOLOGY, 2004, 172 (10) :6065-6073
[20]   Proline residues in CD28 and the Src homology (SH)3 domain of Lck are required for T cell costimulation [J].
Holdorf, AD ;
Green, JM ;
Levin, SD ;
Denny, MF ;
Straus, DB ;
Link, V ;
Changelian, PS ;
Allen, PM ;
Shaw, AD .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (03) :375-384