Eomesodermin controls a unique differentiation program in human IL‐10 and IFN‐γ coproducing regulatory T cells

Abstract

Whether human IL-10-producing regulatory T cells ("Tr1") represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4 + T-cell subsets, including conventional cytotoxic CD4 + T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4 + T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes + GzmK + T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4 + Eomes + T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes + Tr1-like cells are effector cells of a unique GzmK-expressing CD4 + T-cell subset.

EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

“…Gene set enrichement analysis (GSEA) identified similarities of the transcriptional profile of EOMES + CD4 + T-cells with human T R 1 cells (8) (Supplementary Figure 5C) which is indicative for shared functional properties of these two cell populations.…”

“…EOMES belongs to the T-box transcription factor family, which is expressed in many organs including the immune system (19). Redundantly with its paralogue T-BET, EOMES has been shown to promote IFNγ production and cytotoxicity in natural killer (NK) cells (20-22), as well as in CD8 + (21-23) and CD4 + T-cells (7, 8, 21, 24, 25). EOMES has also a non-redundant role in promoting maturation of the classical NK cell subset (26), and in the accumulation of central memory (22, 27) and exhausted, PD-1 expressing CD8 + T-cells (28).…”

“…However, we and others have shown that EOMES can be upregulated in CD4 + T-cells upon activation, which affects their differentiation into helper cell lineages. To this end, it has been shown that EOMES promotes IFNγ expression by Th1 T-cells (31-33) and inhibits differentiation of Th17 (8, 33, 34) and FOXP3 + regulatory T-cells (Treg) (30).…”

“…In cooperation with other factors like PR domain zinc finger protein 1 (BLIMP1), EOMES is a driver of IL-10 production in T R 1 T-cells in mice (7) as well as humans (8). Whether EOMES only promotes Il10 expression by T R 1 cells or is a lineage-defining transcription factor is still unclear (35).…”

Decreased number and impaired function of type 1 regulatory T cells in autoimmune diseases

“…Bacchetta et al (2014) (Table 3). CXCL11, CXCL12, and AhR-c-Maf are used to treat MS (Table 1) that it has great therapeutic potential, but because it is highly dynamic in vivo, there are still few studies available (Gruarin et al, 2019;Zhang et al, 2017). Although there are still many unknowns in Tr1 cell-related therapy, it is a research hotspot in the field of clinical immunology currently, and its public recognition will be definitely deepened in the near future.…”