Protein kinase C-theta critically regulates the proliferation and survival of pathogen-specific T cells in murine listeriosis.
Protein kinase C-theta (PKC-theta) is essential for the activation of T cells in autoimmune disorders, but not in viral infections. To study the role of PKC-theta in bacterial infections, PKC-theta(-/-) and wild-type mice were infected with Listeria monocytogenes (LM). In primary and secondary listeriosis, the numbers of LM-specific CD8 and CD4 T cells were drastically reduced in PKC-theta(-/-) mice, resulting in increased CFUs in spleen and liver of both PKC-theta(-/-) C57BL/6 and BALB/c mice. Furthermore, immunization with peptide-loaded wild-type dendritic cells induced LM-specific CD4 and CD8 T cells in wild-type but not in PKC-theta(-/-) mice. In listeriosis, transfer of wild-type T cells into PKC-theta(-/-) mice resulted in a normal control of Listeria, and, additionally, a selective expression of PKC-theta in LM-specific T cells was sufficient to drive a normal proliferation and survival of these T cells in LM-infected PKC-theta(-/-) recipients, illustrating a cell-autonomous function of PKC-theta in LM-specific T cells. Conversely, adoptively transferred PKC-theta(-/-) T cells were partially rescued from cell death and proliferated in LM-infected wild-type recipients, demonstrating that a PKC-theta deficiency of LM-specific T cells can be partially compensated for by a wild-type environment. Additionally, in vitro experiments showed that only the addition of IL-2, but not an inhibition of caspase-3, induced proliferation and prevented death of PKC-theta(-/-) T cells stimulated with LM-infected wild-type dendritic cells, further demonstrating that the impaired proliferation and survival of PKC-theta(-/-) T cells in listeriosis is not intrinsically fixed and can be experimentally improved.
Sakowicz-Burkiewicz
Monika
M
Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany.
Nishanth
Gopala
G
Helmuth
Ulrike
U
Drögemüller
Katrin
K
Busch
Dirk H
DH
Utermöhlen
Olaf
O
Naumann
Michael
M
Deckert
Martina
M
Schlüter
Dirk
D
D019264:Adoptive Transfer; D000818:Animals; D001117:Arenaviridae Infections / Q000201:enzymology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D049109:Cell Proliferation; D005260:Female; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism
D061945:Caspase Inhibitors; D007376:Interleukin-2; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D053148:Caspase 3