Protective Toxoplasma gondii-Specific T-Cell Responses Require T-Cell-Specific Expression of Protein Kinase C-Theta

• Published in: Infection and Immunity Vol. 78; no. 8; pp. 3454 - 3464
• Main Authors: Nishanth, Gopala, Sakowicz-Burkiewicz, Monika, Händel, Ulrike, Kliche, Stefanie, Wang, Xiaoqian, Naumann, Michael, Deckert, Martina, Schlüter, Dirk
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.08.2010; American Society for Microbiology (ASM)
• Subjects: Animals; Antibodies, Protozoan - analysis; Antibodies, Protozoan - blood; Biological and medical sciences; Brain - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cerebrospinal Fluid - immunology; Cytokines - immunology; Cytokines - secretion; Female; Fundamental and applied biological sciences. Psychology; Immunoglobulin G - analysis; Immunoglobulin G - blood; Isoenzymes - deficiency; Isoenzymes - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Microbial Immunity and Vaccines; Microbiology; Protein Kinase C - deficiency; Protein Kinase C - immunology; Protein Kinase C-theta; Spleen - immunology; Th2 Cells - immunology; Toxoplasma - immunology; Toxoplasma gondii; Protozoa; Apicomplexa; Protein kinase C; Toxoplasma gondii; Enzyme; Transferases; Cellular immunity
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.01407-09

Protein kinase C-theta (PKC-θ) 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 that PKC-θ may be a target for the treatment of T-cell-mediated autoimmune diseases. To explore the function of PKC-θ in a chronic persisting infection in which T cells are crucial for pathogen control, we infected BALB/c PKC-θ⁻/⁻ and PKC-θ⁺/⁺ wild-type mice with Toxoplasma gondii. The PKC-θ⁻/⁻ mice succumbed to necrotizing Toxoplasma encephalitis due to an insufficient parasite control up to day 40, whereas the wild-type mice survived. The number of T. gondii-specific CD4 and CD8 T cells was significantly reduced in the PKC-θ⁻/⁻ mice, resulting in the impaired production of protective cytokines (gamma interferon, tumor necrosis factor) and antiparasitic effector molecules (inducible nitric oxide, gamma interferon-induced GTPase) in the spleen and brain. In addition, Th2-cell numbers were reduced in infected the PKC-θ⁻/⁻ mice, paralleled by the diminished GATA3 expression of PKC-θ⁻/⁻ CD4 T cells and 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-κB, AP-1, and MAPK pathways in T. gondii-infected PKC-θ⁻/⁻ mice. Adoptive transfer of wild-type CD4 plus CD8 T cells significantly protected PKC-θ⁻/⁻ mice from death by increasing the numbers of gamma interferon-producing T. gondii-specific CD4 and CD8 T cells, illustrating a cell-autonomous, protective function of PKC-θ in T cells. These findings imply that PKC-θ inhibition drastically impairs T. gondii-specific T-cell responses with fatal consequences for intracerebral parasite control and survival.