Andrew Hart (Mentor: Terri Laufer, MD)

“Altered chromatin accessibility of CD4 T cell in lupus”

Andrew Hart, Andrew Wells and Terri Laufer

Immune tolerance and homeostasis are disrupted in the initiation of systemic lupus erythematosus. CD4+ T cells become activated and differentiate into Tfh effectors that support autoantibody formation and Th1 and Th17 cells that drive inflammation and pathology. CD4+ T cell activation is associated with altered TCR signaling, metabolism, and cytokine production. How various immune signals, intrinsic and extrinsic to T cells, might influence the progression of T cell dysregulation is poorly understood. Likewise, little is known regarding the potential role of genetic and epigenetic irregularities to propagate T cell dysfunction in lupus. To fill these gaps in knowledge we profiled chromatin and transcriptional states of SLE CD4+ T cells from out-patient lupus subjects. We found that in addition to characterized transcriptional changes in lupus, many patients possess significant chromatin remodeling among CD4+ T cells. Regions of increased accessibility in lupus are enriched for cytokine pathways and NFKB-family involvement. Interestingly, the lupus chromatin signature is present in naïve CD4+ T cells, suggesting that chromatin remodeling is independent of antigen-specific activation and may precede effector differentiation. While we do not find that epigenetic alterations correlate to many inflammatory plasma cytokines such as IFNa, these changes correlate strongly with sIL-2Ra. We suspect that the epigenetic remodeling of naïve CD4+ T cells might contribute to T cell dysfunction and seek to determine the mechanisms which might lead to the establishment of these changes and the timeframe in which they occur during T cell maturation. Ongoing experiments probe the potential hypothesis that active immune responses promote these changes in circulating T cell populations extrinsic signals.