Vitamin A deficiency provokes aberrant T cell responses and exacerbates liver injury in LCMV-infected mice

Abstract

Abstract Vitamin A deficiency (VAD) is a public health problem worldwide; however, its role and underlying mechanisms in viral infection are not entirely understood. In this study, we detected elevated LCMV-specific T cell responses in VAD mice at the acute stage (7 dpi). These VAD mice exhibited higher serum ALT levels and increased liver permeability. Consistently, enhanced antiviral T cell responses were observed in VAD mice in persistent infection (30 dpi), as evidenced by decreased PD-1 expression and increased cytokine production. To investigate whether VAD causes an intrinsic abnormality of T cells during animal development and growth, we transferred spleen cells from control and VAD mice into CD45.1 recipient mice, followed by LCMV infection, and found that antiviral T cell responses were comparable between control and VAD donor cells. However, when CD45.1 cells were transferred into control and VAD recipient mice, they showed a highly activated phenotype in VAD mice. These results suggest that vitamin A or its metabolites restrict T cell activation through an extrinsic way. Retinoic acid (RA) is considered one of the important metabolites of vitamin A. We found that RA administration inhibited excessive T cell responses in VAD mice. To dissect the mechanism of RA, we treated splenocytes and purified CD8+ T cells with RA, followed by PMA stimulation. RA treatment reduced the phosphorylation of AKT, p38, ERK, and S6, as well as the abundance of transcriptional factor NFATc1. Together, our study demonstrated that VAD caused an aberrant T cell response to viral infection, and RA may have the potential to serve as a therapeutic agent for excessive immune responses and tissue injury in VAD patients.