The Journal of Experimental Medicine
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Published 15 March 2004. doi:10.1084/jem.20031022
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 6, 743-752
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PKC{theta} Signals Activation versus Tolerance In Vivo

Nancy N. Berg-Brown1, Matthew A. Gronski1, Russell G. Jones1, Alisha R. Elford1, Elissa K. Deenick1, Bernhard Odermatt2, Dan R. Littman3, and Pamela S. Ohashi1

1 Ontario Cancer Institute, University Health Network, Toronto, Ontario, M5G 2M9 Canada
2 Department of Pathology, University of Zurich, 8091 Zurich, Switzerland
3 Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016

Address correspondence to Pamela S. Ohashi, Ontario Cancer Institute, University Health Network, 610 University Ave., Toronto, Ontario, M5G 2M9 Canada. Phone: (416) 946-4501; Fax: (416) 946-2086; email: pohashi{at}uhnres.utoronto.ca

Understanding the pathways that signal T cell tolerance versus activation is key to regulating immunity. Previous studies have linked CD28 and protein kinase C-{theta} (PKC{theta}) as a potential signaling pathway that influences T cell activation. Therefore, we have compared the responses of T cells deficient for CD28 and PKC{theta} in vivo and in vitro. Here, we demonstrate that the absence of PKC{theta} leads to the induction of T cell anergy, with a phenotype that is comparable to the absence of CD28. Further experiments examined whether PKC{theta} triggered other CD28-dependent responses. Our data show that CD4 T cell–B cell cooperation is dependent on CD28 but not PKC{theta}, whereas CD28 costimulatory signals that augment proliferation can be uncoupled from signals that regulate anergy. Therefore, PKC{theta} relays a defined subset of CD28 signals during T cell activation and is critical for the induction of activation versus tolerance in vivo.

Key Words: anergy • CD28 • CTL • protein kinase C • LCMV

Abbreviations used in this paper: CFSE, carboxyfluorescein diacetate succinimidyl ester; CTL, cytotoxic T lymphocyte; gp, glycoprotein; JNK, c-Jun NH2-terminal kinase; LCMV, lymphocytic choriomeningitis virus; PKC{theta}, protein kinase C-{theta}; SMAC, supramolecular activation complex; VSV, vesicular stomatitis virus.


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