Research led by investigators from Weill Cornell Medicine has identified specific subtypes of CD4+ T cells that play a significant role in the pathogenesis of systemic lupus erythematosus (SLE), a chronic autoimmune disease affecting more than one million people in the United States. The findings, published in Nature Immunology in March 2025, have the potential to shift the focus of lupus research toward more targeted therapies that minimize the risks associated with broad immune suppression.
The study employed single-cell RNA sequencing to analyze CD4+ T-cell subtypes from children diagnosed with SLE, comparing them to samples from healthy controls. While CD4+ T cells have been recognized as contributors to lupus for some time, this research reveals their full complexity and highlights subsets that drive disease progression. According to Dr. Virginia Pascual, co-senior author and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine, targeting a specific CD4+ T-cell subset known as Th10 may offer a promising therapeutic strategy.
Lupus Prevalence and Treatment Challenges
The prevalence of lupus is notably higher among women of childbearing age, with approximately 90% of patients falling into this demographic. The Lupus Foundation of America reports that the disease is particularly severe in individuals of Asian, African, and Native American ancestry. Symptoms range from inflammation in the kidneys, skin, heart, and brain, primarily driven by autoantibodies. Childhood-onset lupus tends to be more aggressive, often leading to lupus nephritis (LN), a severe kidney inflammation.
Current treatment regimens generally rely on broad immunosuppressive therapies, which can leave patients vulnerable to infections and other complications.
Mapping CD4+ T-Cell Subtypes
The research team identified a total of 23 distinct CD4+ T-cell subtypes, each characterized by unique gene-expression signatures. Notably, several of these subsets were found to be significantly expanded in patients with lupus and/or LN. Among these, the Th10 population stands out for its ability to provide both B-cell–helping and cytotoxic functions. Originally characterized in a 2019 study led by co-senior author Dr. Simone Caielli, the Th10 cells appear to offer critical support in inflamed tissues rather than solely in lymph nodes, suggesting their important role in the autoimmune response.
The study also revealed unexpected characteristics of regulatory T cells (Tregs). Typically known for their role in suppressing immune responses, Tregs in lupus patients were observed to be not only abundant but also dysfunctional, often exhibiting pro-inflammatory traits. Dr. Caielli noted that this dysfunction may be linked to microbial dysbiosis, a phenomenon previously reported but not fully understood in SLE patients.
Future Research Directions
This comprehensive analysis, which included hundreds of thousands of single CD4+ T cells, provides a significant new resource for lupus and immunology research. Dr. Jinghua Gu, another co-senior author and assistant professor of research in pediatrics at Weill Cornell Medicine, emphasized the importance of large sample sizes and deep subclustering to identify rare subpopulations associated with specific clinical manifestations in complex diseases like lupus.
The research team is now investigating whether the newly identified lupus-associated T-cell subsets can serve as biomarkers for disease activity and potential therapeutic targets. This groundbreaking work sets the stage for more precise interventions in lupus management, moving beyond traditional approaches and paving the way for tailored therapies that can significantly enhance patient outcomes.
