ABSTRACT/PROJECT SUMMARYThe 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 thatis driven by both genetic and environmental factors. Evidence shows that underlying variation inimmune homeostasis may influence the immune response to challenge. However the identity ofspecific genes involved and mechanism of action are largely unknown. Additionally the interplaybetween environmental stressors genetic variation and aging is largely understudied. The long-termgoal of this study is to understand how genetic and environmental mechanisms regulate immunehomeostasis how this regulation changes with age and how those factors contribute to the immuneresponse to infection. Our lab has previously shown that genetic diversity substantially contributes tovariation in immune responses. Further weve shown that this could be mediated through changes inthe 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 toelucidate the mechanism by which MBD1 regulates B cell differentiation and assess how allelicvariation at Mbd1 alters its functions both in vitro and in vivo. Most studies of immune homeostasisare performed in specific-pathogen free mouse models whose immune systems largely reflect that ofa neonatal human. To address this in the context of immune homeostasis we will examine thecontributions of cytomegalovirus (CMV) and age to the immune environment in the lungs. Here weask whether aging associated changes in the immune environment in the lungs is modified with CMVinfection latency and/or reactivation. Further we will investigate whether these changes contribute toimproved immune responses to respiratory infections in aged mice (Aim 2). Data generated throughthis proposal will shed new light on how immune homeostasis is modified with genetic variation priorimmune exposure and age and will improve our understanding of the role that these factors play inresponse to infection.