Antigen-specific type 1 regulatory T cell responses shape immunity and disease tolerance in human malaria

Type 1 regulatory (Tr1) T cells are a major source of IL-10-mediated immune regulation, yet their phenotypic definition and role in human disease remain incompletely understood. In this issue of the Journal of Clinical Investigation, Nideffer et al. provide insight into human Tr1 cells during pediatric Plasmodium falciparum (Pf) infection. The authors identified Tr1 cells as a major component of the malaria-specific CD4+ T cell response, producing both IL-10 and IFN-γ. They proposed that, in this context, Tr1 cells may be better identified by CD127 downregulation combined with CXCR6 expression than by other surface markers. Importantly, Tr1 cells exhibited suppressive function and were associated with reduced symptomatic disease but also with prolonged infection. Together, these findings refine current models of Tr1 cell identity and establish a more rigorous framework for marker validation using single-cell transcriptomics while highlighting the role of Tr1 cells in balancing immunity and immunopathology during infection.