Abstract 642: CSF-1R+ macrophages control the gut microbiome-enhanced liver NKT function through IL-18

Abstract

Abstract The gut microbiome is an important modulator of the host immune system. Here, we found that altering the gut microbiome by oral vancomycin increases liver NKT cell function. Enhanced NKT cytokine production and activation marker expression were observed in vancomycin-treated mice following both antigen-specific and antigen-independent in vivo NKT stimulations, with a more prominent effect in liver as compared to the spleen. Fecal transplantation studies demonstrated that the NKT functional regulation is mediated by altering the gut microbiome but uncoupled from the modulation of NKT cell population size. Interestingly, when stimulated in vitro, NKT cells from vancomycin-treated mice did not show increased activation, suggesting an indirect regulation. NKT cells expressed high levels of IL-18 receptor, and vancomycin increased the expression of IL-18 in the liver. Blocking IL-18 by neutralizing antibody or using genetically deficient mice attenuated the enhanced NKT activation. Liver macrophages were identified as a major source of IL-18. General macrophage depletion by clodronate abolished this NKT activation. Using anti-CSF-1R depletion or LyzCrexCSF-1RLsL-DTRmice identified CSF-1R+ macrophages as a critical modulator of NKT function. Together, our results demonstrate that the gut microbiome controls liver NKT function via regulating CSF-1R+ macrophages to produce IL-18. Citation Format: Chi Ma, Justin McCallen, John C. McVey, Qianfei Zhang, Benjamin Ruf, Kylynda Bauer, Sophie Wang, Chunwei Walter Lai, Giorgio Trinchieri, Jay A. Berzofsky, Firouzeh Korangy, Tim F. Greten. CSF-1R+ macrophages control the gut microbiome-enhanced liver NKT function through IL-18 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 642.