Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Abstract

CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

Block of both TGF-β and IL-2 signaling impedes Neurophilin-1+ regulatory T cell and follicular regulatory T cell development

“…Eomes can compensate T-bet to induce IFN- γ production in Th1 cells, and expression of Eomes in CD4 + T cells restricts peripheral Foxp3 induction. 45, 46 In our work, we reported upregulated expression of Eomes, CXCR3 on Il2ra −/− Tg Treg cells, which are associated with Th1-like Treg phenotype. In the meantime, Il2ra −/− Tg Treg cells had decreased PD-1, Nrp-1 expression and defective ability to differentiate into Tfr cells.…”

Eomesodermin promotes the development of type 1 regulatory T (T R 1) cells

“…Eomes is a T-box transcription factor which is more often than not coupled with T-bet in the biology of CD8 + T cells and NK cells (34, 35). Its role in regulating functions of CD4 + T cells (36, 37) and suppressing T reg and T H 17 cells differentiation have been described recently (38, 39). Here we demonstrate that IL-10 + IFNγ + T R 1 cells are uniquely dependent on Eomes.…”

Immune modules shared by innate lymphoid cells and T cells

“…Recently, assay for transposase-accessible chromatin with high-throughput sequencing (ATACseq) data from mouse ILCs demonstrated graded expression of ATAC + open chromatin surrounding Eomes , with highest expression in NK cells, lower expression in ILC1, and minimal expression in ILC2 and ILC3 (10), suggesting the potential to express Eomes may not be absent in ILC1. Furthermore, the “Eomes negative” definition of this module is not universally true, as some Th1 cells from both mouse and human express Eomes when activated (67, 68). In human, the two identified ILC1 subsets differ in their expression of EOMES and T-BET; CD127 + ILC1 exclusively expresses T-BET, while intraepithelial ILC1 expresses T-BET as well as higher levels of EOMES compared to CD127 + ILC1 and ILC3 cells (17, 18, 57).…”