Preexisting chronic infection skews the epigenetic landscape of subsequent memory CD8 T cell responses

Previous studies suggest that preexisting chronic disease impairs immune responses to subsequent infection and vaccination. However, the underlying epigenetic mechanisms are understudied. Here, we show that preexisting chronic infection with LCMV clone 13 (CL13) compromised the formation of central memory CD8 T cells (T _CM ) to subsequent Listeria monocytogenes infection, despite not profoundly impacting effector responses. This correlated with a skewed cytokine milieu. Our chromatin-accessibility profiling of Listeria-specific CD8 T cells showed significant epigenetic skewing of both T _CM and effector memory (T _EM ) in mice with preexisting LCMV-CL13, a skewing that started in memory-precursor effector cells (MPECs) during the effector phase. Transcription-factor binding sites (TFBS) analyses highlighted the interferon regulatory factor (IRF) family as major TFs implicated in this skewing. Thus, our results suggest that preexisting persistent inflammation skews the phenotypic and epigenetic landscape of subsequent memory responses, arguing for interventions to optimize vaccine-induced memory in hosts with preexisting chronic disease.