Identifying the role of CD96hi CD4+ T-cells in SLE

Lupus features an overactivation of the immune system, particularly through the increased expression of interferons (IFNs) (proteins that normally help the immune system fight infections) and the production of autoantibodies. This heightened IFN activity is thought to contribute to more than half of lupus-related immune dysfunction, with IFNs playing central roles in driving inflammation and autoimmune responses. These molecules influence various immune cells, including CD4+ T cells, which can exacerbate the disease by promoting the production of autoantibodies and altering immune cell differentiation. Dr. Wacleche will focus on understanding the role of a specific subset of CD4+ T cells, known as CD96hi cells, which may play a protective role in lupus.

Recent findings have shown an immune imbalance in lupus patients, with a higher frequency of cells producing CXCL13, a chemokine that recruits B cells, which in turn generate autoantibodies, and a decreased frequency of IL-22–producing CD96hi cells. IL-22 is a cytokine (signaling protein) involved in maintaining immune tolerance (the immune system’s ability to recognize the body’s own cells and avoid attacking them). By exploring the function of these CD96hi cells using advanced cellular and molecular techniques, Dr. Wacleche aims to determine whether they help balance the immune system and prevent lupus progression. She will also investigate how these cells behave in mouse models of lupus and determine the factors that lead to the production of these CD96hi cells. This could offer new insights into potential therapeutic strategies for restoring balance in lupus patients and may highlight a new marker for re-establishing this balance.

What this means for people with lupus:

Dr. Wacleche’s study could lead to a better understanding of how specific immune cells, like CD96hi T cells, help control lupus and may offer new ways to restore immune balance. By identifying protective cells and the factors that support them, this study could contribute to developing treatments that prevent disease flare-ups and protect against organ damage.

CD96hi cells, which produce the cytokine IL-22, represent a newly characterized subset of CD4+ T cells with a decreased frequency in patients with systemic lupus erythematosus (SLE). Administration of anifrolumab, an anti-type I interferon receptor-blocking antibody, has been shown to increase the frequency of CD96hi cells, suggesting these cells may play a non-pathogenic or protective role in lupus. However, the role of CD96hi cells in immune homeostasis and autoimmunity remains to be fully elucidated. This study hypothesizes that CD96hi cells are non-pathogenic T cells that mitigate SLE pathogenesis. Using advanced cellular and molecular techniques—including adoptive transfer experiments, cell sorting, flow cytometry, and RNA-seq —this project will define the in-depth role of CD96hi cells in lupus. The primary goal is to confirm that CD96hi cells contribute to immune protection in lupus and serve as key markers for re-establishing immune homeostasis. Precisely, The objectives include 1) understanding the role of CD96hi cells in SLE patients, 2) defining the role of CD96hi cells in mice to use as an in vivo animal model, and 3) determining the extrinsic factors leading to CD96hi differentiation. The project includes human cohorts, mice studies, and a series of in vivo and in vitro assays. This research integrates studies on human SLE samples, mouse models, and in vitro assays. By identifying key factors that promote CD96hi cells, the study may nominate these cells as biological markers of SLE remission. Monitoring CD96hi cell frequency could guide clinicians in adjusting medications to optimize therapeutic outcomes and personalize treatment regimens. Findings from this study could propose novel therapeutic targets based on the protective role of CD96hi cells. Additionally, the research has the potential to highlight the therapeutic benefits of dietary interventions, such as consuming nutrient-rich foods that serve as natural sources of AHR ligands. These insights could pave the way for integrating dietary and pharmacological strategies to improve immune health and enhance the quality of life for patients with lupus.