ABSTRACT/PROJECT SUMMARY The immune system is important for protection against infection, cancers, allergy, and autoimmunity. There is significant interindividual variation in the ability to mount an effective immune response that is driven by both genetic and environmental factors. Evidence shows that underlying variation in immune homeostasis may influence the immune response to challenge. However, the identity of specific genes involved, and mechanism of action are largely unknown. Additionally, the interplay between environmental stressors, genetic variation, and aging is largely understudied. The long-term goal of this study is to understand how genetic and environmental mechanisms regulate immune homeostasis, how this regulation changes with age, and how those factors contribute to the immune response to infection. Our lab has previously shown that genetic diversity substantially contributes to variation in immune responses. Further, we’ve shown that this could be mediated through changes in the homeostatic immune environment. Here, we propose that Methyl-CpG binding domain protein 1 (MBD1) is a regulator of effector B cell differentiation at homeostasis (Aim 1). In this aim we seek to elucidate the mechanism by which MBD1 regulates B cell differentiation and assess how allelic variation at Mbd1 alters its functions both in vitro and in vivo. Most studies of immune homeostasis are performed in specific-pathogen free mouse models, whose immune systems largely reflect that of a neonatal human. To address this in the context of immune homeostasis, we will examine the contributions of cytomegalovirus (CMV) and age to the immune environment in the lungs. Here, we ask whether aging associated changes in the immune environment in the lungs is modified with CMV infection, latency, and/or reactivation. Further, we will investigate whether these changes contribute to improved immune responses to respiratory infections in aged mice (Aim 2). Data generated through this proposal will shed new light on how immune homeostasis is modified with genetic variation, prior immune exposure, and age, and will improve our understanding of the role that these factors play in response to infection.