Protective Toxoplasma gondii-specific T-cell responses require T-cell-specific expression of protein kinase C-theta.
Protein kinase C-theta (PKC-theta) 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-theta may be a target for the treatment of T-cell-mediated autoimmune diseases. To explore the function of PKC-theta in a chronic persisting infection in which T cells are crucial for pathogen control, we infected BALB/c PKC-theta(-/-) and PKC-theta(+/+) wild-type mice with Toxoplasma gondii. The PKC-theta(-/-) 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-theta(-/-) 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-theta(-/-) mice, paralleled by the diminished GATA3 expression of PKC-theta(-/-) 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-kappaB, AP-1, and MAPK pathways in T. gondii-infected PKC-theta(-/-) mice. Adoptive transfer of wild-type CD4 plus CD8 T cells significantly protected PKC-theta(-/-) 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-theta in T cells. These findings imply that PKC-theta inhibition drastically impairs T. gondii-specific T-cell responses with fatal consequences for intracerebral parasite control and survival.
Nishanth
Gopala
G
Institut für Medizinische Mikrobiologie, OvG Universität Magdeburg, Leipzigerstrasse 44, Magdeburg 39120, Germany.
Sakowicz-Burkiewicz
Monika
M
Händel
Ulrike
U
Kliche
Stefanie
S
Wang
Xiaoqian
X
Naumann
Michael
M
Deckert
Martina
M
Schlüter
Dirk
D
D000818:Animals; D000913:Antibodies, Protozoan / Q000032:analysis / Q000097:blood; D001921:Brain / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002555:Cerebrospinal Fluid / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood; D007527:Isoenzymes / Q000172:deficiency / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency / Q000276:immunology*; D000074121:Protein Kinase C-theta; D013154:Spleen / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*
D000913:Antibodies, Protozoan; D016207:Cytokines; D007074:Immunoglobulin G; D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta