Single-cell RNA sequencing uncovers diverse CD4⁺ T-cell subtypes in pediatric lupus

Detailed mapping of CD4⁺ T cells from children with systemic lupus erythematosus (SLE) has revealed distinct immune cell subsets with likely roles in disease pathogenesis, according to a study led by Weill Cornell Medicine investigators. The findings are poised to redirect lupus research and open the door to more precise therapies that avoid broad immune suppression.

Published Oct. 21 in Nature Immunology, the study used single-cell RNA sequencing to profile CD4⁺ T-cell subtypes from children with SLE and healthy controls. Although CD4⁺ T cells have long been implicated in lupus, their full diversity and the identity of disease-driving subsets had not been fully defined. The authors note that the results likely apply not only to pediatric lupus but also to adult disease.

Modulation of a particular CD4⁺ T-cell subset called Th10 might be a good strategy for treating patients with lupus, and we are following up with that goal in mind."

Dr. Virginia Pascual, study co-senior author, the Ronay Menschel Professor of Pediatrics and Gale and Ira Drukier Director of Children's Health Research at Weill Cornell Medicine

Systemic lupus affects more than one million people in the United States, according to the Lupus Foundation of America. About 90% of patients are women of childbearing age, and disease risk—and severity—is increased among individuals of Asian, African, and Native American ancestry. Symptoms reflect inflammatory injury to organs such as the kidneys, skin, heart, and brain, largely driven by autoantibodies. Childhood-onset lupus is often more severe and more likely to lead to inflammation in the kidney, also known as lupus nephritis (LN). Current treatments rely on broad immunosuppression, which increases susceptibility to infection.

It is well known that certain CD4⁺ T-cell subsets stimulate B cells to produce antibodies. In lupus, many of these T cells become autoreactive or fail to regulate immunity properly. Identifying the specific subtypes that drive pathology could allow for targeted therapies that preserve overall immune function. Motivated by this possibility, the Pascual laboratory generated an extensive map of CD4⁺ T-cell states and pinpointed those most strongly associated with lupus.

In total, the team identified 23 CD4⁺ T-cell subtypes distinguished by their unique gene-expression signatures. Several were significantly expanded in patients with lupus and/or LN. One key subset was a Th10 population with both B-cell-helper and cytotoxic features that was originally reported in a 2019 study led by co-senior author Dr. Simone Caielli, assistant professor of immunology research in pediatrics at the Drukier Institute within Weill Cornell Medicine. While classical B-cell-helper T cells act in lymph nodes, the researchers found the Th10 population to provide extra-follicular help—likely in inflamed tissues—in lupus patients, underscoring their emerging role in autoimmunity.

The study also uncovered unexpected features of regulatory CD4⁺ T cells (Tregs). Although Tregs normally suppress immune responses, they were abnormally abundant yet dysfunctional in lupus—especially in LN patients—and even exhibited pro-inflammatory traits and receptors typically associated with mucosal environments. "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," said Dr. Caielli.

Altogether, the analysis encompassed hundreds of thousands of single CD4⁺ T cells, creating a major new resource for lupus and immunology research.

"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" said co-senior author Dr. Jinghua Gu, assistant professor of research in pediatrics at Weill Cornell Medicine.

The team is now exploring whether the lupus-associated T-cell subsets they identified can serve as biomarkers for disease activity and as targets for future therapeutic intervention.