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Defective IgG2a/2b Class Switching in PKC^–/– Mice¹

Christa Pfeifhofer^*, Thomas Gruber^*, Thomas Letschka^*, Nikolaus Thuille^*, Christina Lutz-Nicoladoni^*, Natascha Hermann-Kleiter¹, Uschi Braun, Michael Leitges^2, and Gottfried Baier^2,3,*

^* Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University, Innsbruck, Austria; and Department of Experimental Endocrinology, Medical University, Hanover, Germany

Using model tumor T cell lines, protein kinase C (PKC) has been implicated in IL-2 cytokine promoter activation in response to Ag receptor stimulation. In this study, for the first time, PKC null mutant mice are analyzed and display normal T and B lymphocyte development. Peripheral CD3⁺ PKC-deficient T cells show unimpaired activation-induced IL-2 cytokine secretion, surface expression of CD25, CD44, and CD69, as well as transactivation of the critical transcription factors NF-AT, NF-B, AP-1, and STAT5 in vitro. Nevertheless, CD3/CD28 Ab- and MHC alloantigen-induced T cell proliferation and IFN- production are severely impaired in PKC^–/– CD3⁺ T cells. Consistently, PKC-deficient CD3⁺ T cells from OVA-immunized PKC-deficient mice exhibit markedly reduced recall proliferation to OVA in in vitro cultures. In vivo, PKC-deficient mice give diminished OVA-specific IgG2a and IgG2b responses following OVA immunization experiments. In contrast, OVA-specific IgM and IgG1 responses and splenic PKC^–/– B cell proliferation are unimpaired. Our genetic data, thus, define PKC as the physiological and nonredundant PKC isotype in signaling pathways that are necessary for T cell-dependent IFN- production and IgG2a/2b Ab responses.