International Immunology Advance Access originally published online on October 1, 2008
International Immunology 2008 20(12):1507-1515; doi:10.1093/intimm/dxn108
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CD28 stimulation triggers NF-
B activation through the CARMA1–PKC
–Grb2/Gads axis
1 Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan
2 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA
3 Department of Urology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
4 Genome and Drug Research Center, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan
Correspondence to: R. Abe; E-mail: rabe{at}rs.noda.tus.ac.jp
CD28 stimulation contributes to activation of the IL-2 promoter by up-regulating the activity of several transcription factors, including nuclear factor 
B (NF-B)/Rel family members. However, the signal-transducing cascades linking the CD28 molecule and activation of NF-B remain unclear. Protein kinase C (PKC) 
, CARMA1 and Bcl10 have recently been reported to integrate TCR-mediated NF-B activation. However, since the data in these studies were drawn from experiments in which T cells were usually stimulated with both TCR and CD28, the relative contributions of TCR- and CD28-mediated signals to initiation of the NF-B pathway remain elusive. To examine the role of these molecules in NF-B activation through CD28-mediated stimulation, Bcl10 was over-expressed in Jurkat cells and their NF-B activation by CD28- or TCR-cross-linking was evaluated. We found that CD28 stimulation alone can induce NF-B activation in Bcl10-over-expressing Jurkat cells, whereas TCR stimulation alone has only little effect. In addition, we found that Bcl10-induced NF-B activation through CD28-mediated stimulation could be blocked by the dominant-negative form of PKC or CARMA1. Furthermore, genetic studies revealed that Grb2/Gads binding, but not phosphatidylinositol 3-kinase binding, is important in CD28-mediated NF-B activation. These findings indicate that the PKC–CARMA1–Bcl10 signaling pathway participates in the CD28 co-stimulatory signal independently of the TCR-signaling pathway, which leads us to propose that the activation of the NF-B-signaling pathway via PKC-CARMA1–Bcl10 may be markedly dependent on CD28 stimulation rather than TCR stimulation.
Keywords: co-stimulation, signal transduction, T cells, transcription factors
* These authors contributed equally to this study.
Transmitting editor: K. Okumura
Received 3 February 2008, accepted 4 September 2008.