Optimal generation of hepatic tissue-resident memory CD4 T cells requires IL-1 and IL-2

Abstract

Hepatic CD4 tissue-resident memory T cells (TRM) are required for robust protection against <i>Salmonella</i> infection; however, the generation of this T cell population is poorly understood. To interrogate the contribution of inflammation, we developed a simple <i>Salmonella</i>-specific T cell transfer system that allowed direct visualization of hepatic TRM formation. <i>Salmonella</i>-specific (SM1) T cell receptor (TCR) transgenic CD4 T cells were activated in vitro and adoptively transferred into C57BL/6 mice while hepatic inflammation was induced by acetaminophen overdose or <i>L. monocytogenes</i> infection. In both model systems, hepatic CD4 TRM formation was accentuated by local tissue responses. Liver inflammation also enhanced the suboptimal protection provided by a subunit <i>Salmonella</i> vaccine which typically induces circulating memory CD4 T cells. To further elucidate the mechanism of CD4 TRM formation in response to liver inflammation, various cytokines were examined by RNAseq, bone marrow chimeras, and in vivo neutralization. Surprisingly, IL-2 and IL-1 were found to enhance CD4 TRM formation. Thus, local inflammatory mediators enhance CD4 TRM populations and can boost the protective immunity provided by a suboptimal vaccine. This knowledge will be foundational for the development of a more effective vaccine against invasive nontyphoidal salmonellosis (iNTS).