Human CD4+CD3− Innate-Like T Cells Provide a Source of TNF and Lymphotoxin-αβ and Are Elevated in Rheumatoid Arthritis

Innate lymphoid cells encompass a diverse array of lymphocyte subsets with unique phenotype that initiate inflammation and provide host defenses in specific microenvironments. In this study, we identify a rare human CD4+CD3− innate-like lymphoid population with high TNF expression that is enriched in blood from patients with rheumatoid arthritis. These CD4+CD3− cells belong to the T cell lineage, but the lack of AgR at the cell surface renders them nonresponsive to TCR-directed stimuli. By developing a culture system that sustains survival, we show that CD4+CD3− innate-like T cells display IL-7–dependent induction of surface lymphotoxin-αβ, demonstrating their potential to modify tissue microenvironments. Furthermore, expression of CCR6 on the CD4+CD3− population defines a CD127high subset that is highly responsive to IL-7. This CD4+CD3− population is enriched in the peripheral blood from rheumatoid arthritis patients, suggesting a link to their involvement in chronic inflammatory disease.