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Molecular and Cellular Biology, December 2000, p. 9149-9161, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Pleiotropic Contributions of Phospholipase C-gamma 1 (PLC-gamma 1) to T-Cell Antigen Receptor-Mediated Signaling: Reconstitution Studies of a PLC-gamma 1-Deficient Jurkat T-Cell Line

Brenda J. Irvin,1 Brandi L. Williams,2 Allan E. Nilson,3 Hannah O. Maynor,1 and Robert T. Abraham1,*

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 277101; Wellcome/CRC Institute, University of Cambridge, Cambridge, United Kingdom2; and Department of Immunology, Mayo Clinic, Rochester, Minnesota 559053

Received 17 July 2000/Returned for modification 15 August 2000/Accepted 26 September 2000

Phospholipase C-gamma 1 (PLC-gamma 1) plays a crucial role in the coupling of T-cell antigen receptor (TCR) ligation to interleukin-2 (IL-2) gene expression in activated T lymphocytes. In this study, we have isolated and characterized two novel, PLC-gamma 1-deficient sublines derived from the Jurkat T-leukemic cell line. The P98 subline displays a >90% reduction in PLC-gamma 1 expression, while the J.gamma1 subline contains no detectable PLC-gamma 1 protein. The lack of PLC-gamma 1 expression in J.gamma1 cells caused profound defects in TCR-dependent Ca2+ mobilization and NFAT activation. In contrast, both of these responses occurred at normal levels in PLC-gamma 1-deficient P98 cells. Unexpectedly, the P98 cells displayed significant and selective defects in the activation of both the composite CD28 response element (RE/AP) and the full-length IL-2 promoter following costimulation with anti-TCR antibodies and phorbol ester. These transcriptional defects were reversed by transfection of P98 cells with a wild-type PLC-gamma 1 expression vector but not by expression of mutated PLC-gamma 1 constructs that lacked a functional, carboxyl-terminal SH2 [SH2(C)] domain or the major Tyr783 phosphorylation site. On the other hand, the amino-terminal SH2 [SH2(N)] domain was not essential for reconstitution of RE/AP- or IL-2 promoter-dependent transcription but was required for the association of PLC-gamma 1 with LAT, as well as the tyrosine phosphorylation of PLC-gamma 1 itself, in activated P98 cells. These studies demonstrate that the PLC-gamma 1 SH2(N) and SH2(C) domains play functionally distinct roles during TCR-mediated signaling and identify a non-Ca2+-related signaling function linked to the SH2(C) domain, which couples TCR plus phorbol ester-CD28 costimulation to the activation of the IL-2 promoter in T lymphocytes.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, Room C333B LSRC, Box 3813, Duke University Medical Center, Durham, NC 27710. Phone: (919) 613-8650. Fax: (919) 681-8461. E-mail: abrah008{at}mc.duke.edu.

Molecular and Cellular Biology, December 2000, p. 9149-9161, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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