Implications for Speckled proteins 110 and 140 in adaptive immunity

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The Speckled protein (SP) family of nuclear body proteins has recently garnered interest for their role(s) as chromatin regulators that mediate transcriptional programs of gene silencing or activation in specified immune cell populations. The human SP family consists of 4 members - SP100, SP110, SP140 and SP140L, whilst the mouse SP family comprises Sp100, Sp110, and Sp140. Both innate and adaptive immune cell lineages as well as non-immune cells express SP100 and SP110, whereas SP140 is entirely immune-restricted. Results from RNA sequencing analysis revealed that human SP family members are highly expressed in developing and mature B cells, activated CD4+ and CD8+ T cells, and myeloid lineages. SPs were also identified as interferon (IFN)-stimulated genes (ISGs), implicating them in pathogen-induced immunity, autoimmunity and infection. Indeed, mutations in all human SP family members are associated with autoimmune, inflammatory, immunodeficiency, and infectious diseases, highlighting essential roles for this family of proteins in immune cell homeostasis and response to infections. However, SPs are currently understudied in the context of immune cell regulation, and particularly in adaptive immune cells, in which they are abundantly expressed, and knowledge is completely lacking. We recently identified SP110 and SP140 as two new candidate downstream mediators of the transcription factor interferon regulatory factor 5 (IRF5) through scRNAseq of T cell receptor (TCR)- stimulated primary murine CD4+ T cells from Irf5+/+ and Irf5-/- littermate mice. IRF5 is a key mediator of both innate and adaptive immunity and a genetic risk factor associated with susceptibility to a wide variety of inflammatory and autoimmune diseases; the most well-studied being systemic lupus erythematosus (SLE). The premise of this application is that SP110 and SP140 act downstream of IRF5 to mediate B and T cell dysregulation commonly seen in patients with SLE, such as increased T cell activation, elevated levels of circulating plasma cells and pathogenic autoantibodies. In this proposal, we will 1) test the hypothesis that SP110 and SP140 act downstream of IRF5 to mediate T and B cell activation, proliferation, and effector function and 2) determine if SP110 and SP140 are dysregulated in immune cells of SLE patients and if expression correlates with IRF5 expression and/or activation, autoantibody production, and disease activity. Successful completion of these studies will provide new mechanistic insight into the function(s) of SP110 and SP140 in adaptive immune cells, in which knowledge is completely lacking. Further, we will provide an understanding of how these factors contribute to immune disorders that will provide rationale for the design of new putative therapies for diseases associated with SP loss or over-activation, as SPs offer a novel and more refined therapeutic avenue for taming hyper-active immune responses.