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

Hepatic CD4 tissue-resident memory T cells (TRM) are required for robust protection against infection; however, the generation of this T cell population is poorly understood. To interrogate the contribution of inflammation, we developed a simple -specific T cell transfer system that allowed direct visualization of hepatic TRM formation. -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 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 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).