The Function of Phosphatidylinositol 3-Kinase delta (PI3Kδ) Enzyme in Protective Immunity to Trypanosoma congolense Infection in Mice: The Role of Regulatory B cells

Autor: Folayemi Olayinka-Adefemi, Chukwunonso Onyilagha, Nipun Jayachandran, Sen Hou, Ping Jia, Jude E Uzonna, Aaron J Marshall
Rok vydání: 2020
Předmět:
Zdroj: The Journal of Immunology. 204:82.39-82.39
ISSN: 1550-6606
0022-1767
Popis: The delta isoform of PI 3-kinase (PI3Kδ) has important functions in B cell activation. Trypanosoma parasites utilize several mechanisms to exploit and evade host B cell and antibody responses critical for immunity. We sought to determine the impact of PI3Kδ in immunity to Trypanosoma congolense infection. We found that PI3KδD910A mutant mice show a surprisingly enhanced control of parasitemia in early infection (7–9 days) when compared to wild-type (WT) C57BL/6 mice. Drug treatment with Idelalisib to acutely inhibit PI3Kδ during infection in WT mice led to improved early control of parasitemia, consistent with results from genetically deficient mice. Both mutant mice and Idelalisib-treated mice showed a delay in polyclonal B cell activation and CD80/86 expression. Analysis of cytokine levels in the blood and peritoneal cavity showed higher IFNg and lower IL-10 levels in the drug-treated group at early time points, indicating a more pro-inflammatory environment. B1 cells were identified as the major IL-10 producing cells in the peritoneal cavity in early infection, and B1 cell production of IL-10 was significantly impaired by PI3Kδ-inhibitor treatment. We further observed increased Nitric oxide production in drug-treated mice, which correlated with increased parasite killing in early infection. Despite the improved early parasite control, there was a 100% mortality in PI3KδD910A mutants and 25% mortality in Idelalisib treated mice, presumably due to compromised generation of parasite-specific antibodies required to clear the first wave of blood infection. Our findings suggest that PI3Kδ inhibition impacts both regulatory B cell functions, affecting the early innate response, and generation of critical protective antibodies.
Databáze: OpenAIRE
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