ABSTRACT Our prior work using physical maps of systemic lupus erythematosus (SLE)-associated genetic variation in the context of the 3D structure of the genome in the nucleus of disease-relevant immune cell types have implicated the kinase HIPK1 as a factor controlling SLE susceptibility. This kinase has been studied in the context of cancer, but a role for HIPK1 in immunity, tolerance, or SLE has not been explored. In this exploratory, high-risk/high- impact application we will use genetic and pharmacologic targeting approaches to establish whether HIPK1 regulates T cell differentiation, T cell-dependent humoral immune responses, and SLE pathophysiology in powerful human and mouse models of follicular lymphocyte differentiation and function. The outcome of these studies is likely to forward basic understanding of the regulation of humoral immunity and suggest a completely novel immunomodulatory approach for the management of SLE disease.