Protective Toxplasma gondii-specific T cell responses require the T cell-specific expression of protein kinase C-{theta}1

Infect Immun. 2010 May 24. [Epub ahead of print]

Protective Toxplasma gondii-specific T cell responses require the T cell-specific expression of protein kinase C-{theta}1

Nishanth G, Sakowicz-Burkiewicz M, Händel U, Kliche S, Wang X, Naumann M, Deckert M, Schlüter D.

Institut für Medizinische Mikrobiologie, OvG Universität Magdeburg, Magdeburg, Germany; Institut für Molekulare und Klinische Immunologie, OvG Universität Magdeburg, Magdeburg, Germany; Institut für Experimentelle Innere Medizin, OvG Universität Magdeburg, Magdeburg, Germany; Abteilung für Neuropathologie, Universitätsklinikum Köln, Köln, Germany.

Abstract
Protein kinase C (PKC)- is important for the activation of autoreactive T cells but is thought to be of minor importance for T cell responses in infectious diseases suggesting PKC- as target for the treatment of T cell-mediated autoimmune diseases. To explore the function of PKC- in a chronic persisting infection, in which T cells are crucial for pathogen control, we infected BALB/c PKC-(-/-) and PKC-(+/+) wildtype mice with Toxoplasma gondii. PKC-(-/-) mice succumbed to necrotizing Toxoplasma encephalitis due to an insufficient parasite control up to day 40, whereas wildtype mice survived. The number of T. gondii-specific CD4 and CD8 T cells was significantly reduced in PKC-(-/-) mice resulting in an impaired production of protective cytokines (interferon-gamma, tumor necrosis factor) and anti-parasitic effector molecules (inducible nitric oxide, IGTP) in spleen and brain. In addition, Th2 cells were reduced in infected PKC-(-/-) mice, paralleled by a diminished GATA3 expression of PKC-(-/-) CD4 T cells and a reduced T. gondii-specific IgG production in serum and cerebrospinal fluid. Western blot analysis of splenic CD4 and CD8 T cells revealed an impaired activation of the NF-kappaB, AP1, and MAPK pathway in T. gondii-infected PKC-(-/-) mice. Adoptive transfer of wildtype CD4 plus CD8 T cells significantly protected PKC-(-/-) mice from death by increasing numbers of interferon-gamma-producing T. gondii-specific CD4 and CD8 T cells illustrating a cell-autonomous, protective function of PKC- in T cells. These findings imply that PKC- inhibition drastically impairs T. gondii-specific T cells responses with fatal consequences for intracerebral parasite control and survival.

PMID: 20498263 [PubMed - as supplied by publisher]