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Michael Waterfield, MD, PhD

Assistant Professor

University of California, San Francisco

Pediatrics

https://andersonlab.ucsf.edu/people/michael-waterfield-md-phd

Epigenetic Regulation of Il2 by ATF7ip – Implications for SLE

Interleukin-2, which is mostly made by the immune cells called T cells, seems to calm the immune system and has shown promise as a lupus treatment. We have discovered in mice that another protein known as ATF7ip reduces T cells’ production of interleukin-2. Dr. Waterfield’s new study will identify molecules that partner with ATF7ip in T cells, which could lead to drugs that block this protein and spur cells to make more interleukin-2. In the second part of their study, they will genetically modify the T cells of mice with lupus to remove ATF7ip. If symptoms improve, they will know that targeting this protein can offer a new treatment strategy for patients with lupus.

What this study means for people with lupus

Some immune cells in patients with lupus mistakenly attack their own tissues. But other cells release a chemical called interleukin-2 that stops these attacks. Dr. Waterfield and his colleagues are investigating a new way to boost cells’ production of interleukin-2. Their results could help researchers create new drugs to treat lupus by raising interleukin-2 levels.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that causes organ inflammation and the production of autoantibodies to nuclear proteins. The etiology of SLE is complex and is due to a combination of genetic and environmental factors. Currently, there are few targeted therapies for SLE and there is a need to develop new therapeutic modalities. Multiple immune cell types are dysregulated in SLE. One cell type that has been implicated in SLE pathogenesis is the T cell and a characteristic of SLE T cells is the inability to produce significant interleukin 2 (IL-2). IL-2 has multiple functions in promoting immune tolerance and thus, low IL-2 levels in SLE patients may partially cause the autoimmunity seen in these patients. Furthermore, there are case-reports of low dose IL-2 being an effective treatment for SLE. Thus, mechanisms to increase Il2 gene expression in T cells may be useful therapeutically. Epigenetics is defined by factors that alter gene expression without changing the underlying genetic code. Two well-characterized epigenetic modifications are histone methylation and DNA methylation. Histone methylation occurs in a variety of flavors with some marks inducing gene activation while others induce gene repression. The main histone marks of gene repression are H3K9me3 and H3K27me3. We created a conditional knockout mouse for the activating transcription factor 7 interacting protein (ATF7ip), a protein that is essential to create the H3K9me3 mark. Interestingly, T cell specific deletion of ATF7ip results in a severe defect in T helper 17 (Th17) differentiation without affecting other T cell lineages. RNA-seq analysis of CD4-cre ATF7ipfl/fl T cells revealed that these cells overproduce Il2 with TCR stimulation. IL-2 is a known inhibitor of Th17 differentiation so increased IL-2 may explain the Th17 defect in CD4-cre ATF7ipfl/fl T cells. ChIP-seq analysis of CD4-cre ATF7ipfl/fl T cells showed less H3K9me3 at the Il2-Il21 intergenic region potentially explaining the increased expression of Il2. Due to the increased production of IL-2 by CD4-cre ATF7ipfl/fl T cells, inhibition of ATF7ip could be exploited therapeutically to treat SLE. The specific aims of this grant will 1) use mass spectrometry to identify novel ATF7ip binding partners, and 2) interrogate the effect of Atf7ip deletion on the development of autoimmunity in lupus prone mice. This work will generate important preliminary data prior to developing inhibitors of ATF7ip to treat SLE or other autoimmune disease.

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