Type I regulatory T cells in malaria: of mice and men

Abstract

Type I regulatory T (Tr1) cells are a population of regulatory CD4+ T cells implicated in the suppression of pathological immune responses across multiple diseases, but a unifying transcriptional signature of Tr1 identity across disease contexts has not been characterized. In this issue of the JCI, Edward, Ng, and colleagues identified a conserved transcriptional signature that distinguished Tr1 (IL-10+IFN-γ+) from Th1 (IL-10-IFN-γ+) cells in human and mouse malaria. This signature implicated genes encoding inhibitory receptors - including CTLA-4 and LAG-3 - and transcription factors - including cMAF. The authors identified coinhibitory receptor expression that distinguished Tr1 cells from other CD4+ T cell subsets. Furthermore, cMAF - and, to a lesser extent, BLIMP-1 - promoted IL-10 production in human CD4+ T cells. BLIMP-1 also played a role in supporting the expression of inhibitory receptors. These findings describe a few key features that seem to be conserved by Tr1 cells across multiple species, disease contexts, and marker definitions.

Figure 1. Select features of Tr1 biology are conserved across disease models.

Tr1 cells from four different contexts, including mouse malaria, human malaria, human dengue infection, and human CD4⁺ T cells cultured ex vivo under differentiating conditions in the presence of activating tolerogenic DC-10 and IL-10, share a common phenotype. This interspecies Tr1 signature is characterized by the expression of coinhibitory and stimulatory receptors (CTLA-4, LAG-3, TIM-3, ICOS) and by the production of IL-10 and IFN-γ. In ex vivo Tr1 differentiation experiments, BLIMP-1 and cMAF promoted the expression of IL-10, and BLIMP-1 played an additional role in positively regulating coinhibitory receptor expression.