A recent study led by investigators at Weill Cornell Medicine has identified specific immune cell subtypes that may play a crucial role in the development of systemic lupus erythematosus (SLE), a chronic autoimmune disease. This groundbreaking research, published in the journal Nature Immunology in March 2025, utilized advanced single-cell RNA sequencing techniques to map CD4+ T cells in children diagnosed with lupus. The findings are expected to transform lupus research and pave the way for more precise treatments that do not compromise the overall immune system.
The research team concentrated on profiling CD4+ T-cell subtypes not only from children with SLE but also from healthy controls. Despite the longstanding recognition of CD4+ T cells in lupus pathology, the intricate diversity of these immune cells and the specific subtypes responsible for disease progression had remained largely undefined until now. The authors suggest that these findings could be relevant for both pediatric and adult forms of lupus.
Dr. Virginia Pascual, co-senior author and the Gale and Ira Drukier Director of Children’s Health Research at Weill Cornell Medicine, emphasized the implications of targeting a particular CD4+ T-cell subset known as Th10. “Modulation of Th10 might be a good strategy for treating patients with lupus, and we are following up with that goal in mind,” she stated.
Lupus affects over one million individuals in the United States, with approximately 90% of those affected being women of childbearing age. The disease disproportionately impacts individuals of Asian, African, and Native American descent, often leading to severe symptoms that damage organs such as the kidneys, skin, heart, and brain. Current treatment methods primarily involve broad immunosuppression, which heightens the risk of infections.
The study revealed significant insights into the roles of CD4+ T-cell subtypes in the context of lupus. It is well-established that certain subsets of these T cells stimulate B cells to produce antibodies. In lupus, many CD4+ T cells become autoreactive or inadequately regulate immune responses. By pinpointing the specific subtypes responsible for disease pathology, the potential for developing targeted therapies that maintain overall immune function emerges.
The research team identified a total of 23 distinct CD4+ T-cell subtypes, characterized by unique gene-expression profiles. Several of these subtypes were found to be significantly expanded in lupus patients and those with lupus nephritis (LN). Among them, the Th10 subset exhibited both B-cell helper and cytotoxic features, previously noted in a 2019 study led by Dr. Simone Caielli, an assistant professor of immunology research in pediatrics at the Drukier Institute at Weill Cornell Medicine. This Th10 population appears to provide additional help to B cells outside of lymph nodes, particularly in inflamed tissues, highlighting its emerging role in autoimmunity.
The study also examined regulatory T cells (Tregs), which typically function to suppress immune responses. Surprisingly, Tregs were found to be unusually abundant yet dysfunctional in lupus patients, particularly those with LN. They displayed pro-inflammatory characteristics and receptors normally associated with mucosal environments. Dr. Caielli noted, “The dysfunction of SLE Treg cells is likely connected to microbial dysbiosis, a phenomenon already reported in patients with SLE but not yet well elucidated.”
The extensive analysis of hundreds of thousands of single CD4+ T cells offers a significant new resource for both lupus and immunology research. Dr. Jinghua Gu, co-senior author and assistant professor of research in pediatrics at Weill Cornell Medicine, remarked on the study’s implications. “Single-cell profiling is now very widespread, but a new lesson we learned here is that you may need very large numbers of cells combined with deep subclustering to associate a rare subpopulation with specific clinical manifestations, especially in a disease as heterogeneous as lupus.”
As the research progresses, the team aims to investigate whether the lupus-associated T-cell subsets identified in this study could serve as biomarkers for disease activity and as targets for future therapeutic interventions. The findings represent a promising step forward in understanding lupus and developing more effective treatments that could improve the lives of those affected by this complex autoimmune disease.
