Protein kinase C θ deficiency increases resistance of C57BL/6J mice to Plasmodium berghei infection-induced cerebral malaria.

Abstract

Protein kinase C θ (PKCθ) functions as a core component of the immunological synapse and serves as a key protein in the integrated T-cell antigen receptor (TCR)/CD28-induced signaling cascade leading to T-cell activation. However, the involvement of PKCθ in host-mediated immune responses to pathogens has not been thoroughly investigated. We tested the consequences of PKCθ ablation on the host response to infection by Plasmodium berghei ANKA (PbA). We found that both PKCθ(+/+) and PKCθ(-/-) C57BL/6J mice are susceptible to infection with PbA. However, despite a similar parasite burden, PKCθ(+/+) mice had an earlier onset of neurological signs, characteristics of experimental cerebral malaria (ECM), resulting in an earlier death. These mice suffered from an early and pronounced splenomegaly with a concomitant increase in the total number of CD4(+) splenic T cells. In contrast, a large proportion of PbA-infected PKCθ(-/-) mice overcame the acute phase characterized by neurological symptoms and survived longer than PKCθ(+/+) mice. The partial resistance of PKCθ(-/-) mice to ECM was associated with an impaired production of Th1-type cytokines, including gamma interferon and tumor necrosis factor alpha/lymphotoxin-α, which are known to exacerbate symptoms leading to ECM. In addition, PbA infection-induced LFA-1 expression in CD8(+) T cells was suppressed in PKCθ-deficient T cells, suggesting a diminished ability to adhere to endothelial cells and sequester in brain microvasculature, which may explain the decrease in neurological symptoms. These data implicate PKCθ in CD4(+) Th1(+) and CD8(+) T-cell-mediated immune responses during PbA infection that contribute to the development of ECM.

• Authors: Ariel Ohayon, Jacob Golenser, Rosa Sinay, Ami Tamir, Amnon Altman, Yaakov Pollack, Noah Isakov
• Journal: Infection and immunity (Infect Immun) Vol. 78 Issue 10 Pg. 4195-205 (Oct 2010) ISSN: 1098-5522 [Electronic] United States
• PMID: 20660606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Lymphocyte Function-Associated Antigen-1
• Prkcq protein, mouse
• Protein Kinase C
• Protein Kinase C-theta

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Gene Expression Regulation (immunology)
• Genetic Predisposition to Disease
• Isoenzymes (genetics, metabolism)
• Lymphocyte Function-Associated Antigen-1 (metabolism)
• Malaria (immunology, parasitology)
• Malaria, Cerebral (immunology, parasitology)
• Mice
• Mice, Inbred C57BL
• Organ Size
• Plasmodium berghei (immunology)
• Protein Kinase C (genetics, metabolism)
• Protein Kinase C-theta
• Spleen (pathology)
• Th1 Cells (immunology)
• Up-Regulation