PI3Kδ is critical in generating humoral and regulatory immune responses. In this study, we determined the impact of PI3Kδ in immunity to Trypanosoma congolense, an African trypanosome that can manipulate and evade Ab responses critical for protection. Upon infection with T. congolense, PI3Kδ^D910A mice lacking PI3Kδ activity paradoxically show a transient enhancement in early control of parasitemia, associated with impaired production of regulatory IL-10 by B cells in the peritoneum. C57BL/6 wild-type (WT) mice treated with the PI3Kδ inhibitor (PI3Kδi) Idelalisib showed a similar transient decrease in parasitemia associated with reduced IL-10. Strikingly, however, we find that PI3Kδ^D910A mice were ultimately unable to control this infection, resulting in uncontrolled parasitemia and death within 2 wk. Assessment of humoral responses revealed delayed B cell activation, impaired germinal center responses, and compromised Ab responses to differing degrees in PI3Kδ^D910A and PI3Kδi-treated mice. To test the role of Abs, we administered serum from WT mice to PI3Kδ^D910A mice and found that lethality was prevented by postinfection serum. Interestingly, serum from naive WT mice provided partial protection to PI3Kδ^D910A mutants, indicating an additional role for natural Abs. Together our findings suggest that although PI3Kδ drives immune regulatory responses that antagonize early control of parasite growth in the peritoneum, it is also required for generation of Abs that are critical for protection from systemic trypanosome infection. The essential role of PI3Kδ for host survival of African trypanosome infection contrasts with findings for other pathogens such as Leishmania, underlining the critical importance of PI3Kδ-dependent humoral immunity in this disease.

PI3Kδ 对产生体液和调节免疫反应至关重要。在这项研究中，我们确定了 PI3Kδ 对刚果锥虫免疫的影响，刚果锥虫是一种非洲锥虫，可以操纵和逃避对保护至关重要的 Ab 反应。一旦感染T. congolense，PI3Kδ ^D910A缺乏PI3Kδ活性的小鼠矛盾显示寄生虫血症的早期控制瞬态增强，通过在腹膜B细胞受损的生产调节IL-10的相关联。用 PI3Kδ 抑制剂 (PI3Kδi) Idelalisib 治疗的 C57BL/6 野生型 (WT) 小鼠表现出类似的与减少的 IL-10 相关的寄生虫血症的瞬时减少。然而，引人注目的是，我们发现 PI3Kδ ^D910A小鼠最终无法控制这种感染，导致寄生虫血症不受控制并在 2 周内死亡。体液反应的评估显示，在 PI3Kδ ^D910A和 PI3Kδi 处理的小鼠中，B 细胞活化延迟、生发中心反应受损和 Ab 反应受损程度不同。为了测试 Abs 的作用，我们将 WT 小鼠的血清给予 PI3Kδ ^D910A小鼠，发现感染后血清可防止致死。有趣的是，来自未经^处理的WT 小鼠的血清为 PI3Kδ ^D910A提供了部分保护突变体，表明天然 Ab 的额外作用。综上所述，我们的研究结果表明，虽然 PI3Kδ 驱动免疫调节反应，对抗腹膜中寄生虫生长的早期控制，但它也是产生对预防系统性锥虫感染至关重要的 Ab 所必需的。PI3Kδ 对非洲锥虫感染宿主存活的重要作用与其他病原体（如利什曼原虫）的发现形成对比，强调了 PI3Kδ 依赖性体液免疫在该疾病中的关键重要性。