Systemic lupus erythematosus (SLE) is driven by an abnormal immune response involving T cells and B cells. Regulatory T cells (Tregs) usually help control the immune system and prevent autoimmune diseases by suppressing the activation of harmful T and B cells. Dr. Rao and co-investigator Dr. Michael Brenner hypothesize that, in SLE, the inflammatory environment causes Tregs to become dysfunctional, preventing them from effectively controlling the disease. They previously found that people with SLE have an increased number of abnormal Tregs with reduced production of molecules needed for them to suppress overactive T and B cells. This suggests that inflammation might cause Treg dysfunction in SLE.

Dr. Rao and Dr. Brenner’s research will investigate how inflammatory signals affect Treg function in SLE. They will compare the function of normal and abnormal Tregs from people with SLE, focusing on the expression of molecules necessary for suppressing immune responses. They will also study how inflammatory signals may induce the dysfunctional state in Tregs and whether blocking specific pathways can prevent this dysfunction. Dr. Rao and Dr. Brenner will examine the clinical significance of these abnormal Tregs in SLE patients, including their presence in blood and kidney tissues and how they correlate with disease severity and response to treatment.

What this means for people with lupus

Dr. Rao and Dr. Brenner’s research could lead to new strategies for restoring Treg function in SLE, potentially improving the effectiveness of Treg-based therapies and achieving better control of the disease. By understanding and reversing Treg dysfunction, this study aims to lay the groundwork for more precise treatments that can help re-establish immune tolerance in SLE patients, offering hope for improved outcomes and quality of life.

SLE is driven by a pathologic autoimmune response mediated by autoreactive T cells and B cells. T regulatory cells (Tregs) are a specialized subset of T cells whose job it is to suppress autoimmune lymphocytes; however, Tregs fail to suppress the pathologic response in patients with SLE. Aberrant or disrupted function of Tregs may contribute to disease in SLE; however, the features and extent of dysregulation of Tregs in SLE remain ambiguous. Here, we demonstrate that an aberrant CD25low Treg population is highly expanded in the circulation of SLE patients. Our preliminary data indicate a novel hypothesis that inflammatory signals in SLE patients disrupt the phenotype and function of Tregs. In this project, we use functional studies of Tregs from patients with SLE and correlative studies of SLE cohorts to define the extent of Treg dysfunction in SLE and evaluate the ability of specific inflammatory signals to induce this dysfunction. We further evaluate the clinical correlations of the expanded CD25low Treg population in cohorts of patients with SLE to place this dimension of Treg dysfunction in the context of clinical lupus and lupus nephritis manifestations. We expect that this project will yield a new perspective on Treg dysfunction in SLE patients with immediate implications for therapeutic strategies to enhance beneficial Treg functions in SLE.