Eomesodermin‐expressing type 1 regulatory (EOMES⁺Tr1)‐like T cells: Basic biology and role in immune‐mediated diseases

Abstract

Type 1 regulatory (Tr1) T cells are currently defined all T cells with regulatory functions that lack FOXP3 expression and produce IL‐10. Tr1 cells are heterogeneous, and the different reported properties of Tr1‐cell populations have caused some confusion in the field. Moreover, understanding the role of Tr1 cells in immune‐mediated diseases has been hampered by the lack of a lineage‐defining transcription factor. Several independent studies indicated recently that the transcription factor Eomesodermin (EOMES) could act as a lineage‐defining transcription factor in a population of IL‐10 and IFN‐γ co‐producing Tr1‐like cells, since EOMES directly induces IFN‐γ and cytotoxicity, enhances IL‐10, and antagonizes alternative T‐cell fates. Here, we review the known properties of EOMES+Tr1‐like cells. They share several key characteristics with other Tr1 cells (i.e., “Tr1‐like”), namely high IL‐10 production, cytotoxicity, and suppressive capabilities. Notably, they also share some features with FOXP3+Tregs, like downregulation of IL‐7R and CD40L. In addition, they possess several unique, EOMES‐dependent features, that is, expression of GzmK and IFN‐γ, and downregulation of type‐17 cytokines. Published evidence indicates that EOMES+Tr1‐like cells play key roles in graft‐versus‐host disease, colitis, systemic autoimmunity and in tumors. Thus, EOMES+Tr1‐like cells are key players of the adaptive immune system that are involved in several different immune‐mediated diseases.

Consequences of COVID-19 on Adipose Tissue Signatures

“…The upregulation in EOMES , a transcription factor involved in the T-cell exhaustion process in severe COVID-19 patients, in the comparison describing infected and not vaccinated cases, suggests that EOMES may play a role in the development of T-cell exhaustion, as described before [ 45 ]. It directly induces IFN-γ and cytotoxicity, enhances IL-10, and antagonizes alternative T-cell fates [ 46 ].…”

Autosomal Dominant-Hyper-IgE Syndrome patients contain pre-Th17-cells that are activated by opportunistic pathogens to produce IL-10

“…helper T-cells are unrelated to EOMES + Tr1-like cells, which also produce IL-10 but do not express CCR6 and are probably generated from Th1-cells upon chronic TCR stimulation 40,[42][43][44][45] . Here, we showed that CCR6 + T-cells that lack differentiation markers of established CCR6 + T-cell subsets (CCR6 SP ) and produce IL-10 represent an early stage of Th17 differentiation, since they displayed a TCM phenotype but expressed nevertheless some ROR-t, suggesting that they are pre-committed to a Th17 fate.…”

“…Surprisingly, CCR6 + T-cells in AD-HIES patients produced significantly increased levels of IL-10 (Figure 6B). Notably, IL-10 production by CCR6 -T-cells, as well as FOXP3 + Tregs and EOMES + Tr1-like cells 40 was instead comparable in AD-HIES patients and HDs (sFigure 6B). Since CCR6 + T-cells have peculiar stimulation requirements for IL-10 production 41 , we analysed IL-10 production also after stimulation of the TCR of purified T-cell subsets with anti-CD3 antibodies in the presence of IL-2 26 , and upon stimulation of total PBMC with the superantigen SEB, which induces a productive interaction between the TCR and MHC class-II molecules.…”

Cytotoxic CD4 T cells in the mucosa and in cancer

“…In addition to roles for AHR and c-MAF described above, recent evidence demonstrates the importance of the transcription factor EOMES at mediating Tr1 development, and in particular, at inducing cytotoxic potential among Tr1s [reviewed in ( 83 )]. The majority of evidence to date has not clarified whether Tr1 cells are a distinct differentiation lineage, or simply a transient activation state.…”