Eomesodermin-expressing T-helper cells are essential for chronic neuroinflammation

Abstract

Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes+ CD4+ T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes+ CD4+ T cells.

Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes

“…Moreover, EOMES has been identified as a susceptibility gene in MS (Parnell et al, 2014; Patsopoulos et al, 2011). In addition, an increased proportion of Eomes + CD4 + T cells has reported in patients with secondary progressive MS as compare to relapsing remitting MS or healthy controls and these cells accumulates in the CSF from MS patients further supporting the role of this transcription factor in CNS inflammation in human (Raveney et al, 2015). …”

“…The role of this T-Box transcription factor in CNS neuroinflammation has recently been demonstrated. Indeed, mice harboring a T cell-specific deletion of Eomes developed EAE with reduced severity, a similar phenotype as Foxo3-deficient mice (Raveney et al, 2015). Moreover, EOMES has been identified as a susceptibility gene in MS (Parnell et al, 2014; Patsopoulos et al, 2011).…”

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.…”

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

“…1 T cells to acquire cytotoxicity [42][43][44] and these cytolytic CD4 1 T cells also upregulate CD94 and NKG2A. 45,46 However, in contrast to induction of cytotoxicity via IL-12, mainly IL-2 has been implicated in this process.…”