Authors

Discussion

Chronic infections with the parasite Trypanosoma brucei, the causative agent of Human African trypanosomiasis, lead to severe neuroinflammation and death if left untreated. However, a detailed understanding of the cellular and molecular interactions that mediate this severe pathology is lacking. Using single cell and spatial transcriptomics, we have identified for the first time, a unique population of CD138⁺plasma cells in the brain ventricles of infected animals compared to naïve controls. These plasma cells express a robust innate-like, regulatory transcriptional profile, characterised by the expression of pathogen-sensing molecules (Tlr4), anti-inflammatory cytokines (Il10) and pro-survival receptor molecules such asTnfrsf17 (B cell maturation antigen, BCMA). Additionally, we detected a subpopulation of Cx3cr1⁺ microglia that express a wide range of factors associated with B cell recruitment and survival, such as Cxcl12 and Tnfsf13b (B cell activating factor). Interestingly, Cx3cr1⁺ microglia are the only cells in our dataset expressing both Il10ra and Il10rb, suggesting that they are primed to respond to IL-10. Further in vitro studies demonstrated that these regulatory, innate-like plasma cells can stimulate microglia polarisation towards an anti-inflammatory state via IL-10 signalling. We propose a model in which unresolved brain infections induce the activation of Cx3cr1⁺ microglia, leading to the recruitment and survival of plasma cells mediated by CXCL12 and BAFF-BCAM signalling, respectively. In turn, these regulatory plasma cells alleviate inflammation by dampening Cx3cr1⁺ activation via IL-10 signalling, limiting pathology. This work provides novel insights into the mechanisms of B cell-stromal interactions in the brain during infection.