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

Abstract

SUMMARY The transcription factor Foxo3 plays a crucial role in myeloid cell function but its role in lymphoid cells remains poorly defined. Here, we have shown that Foxo3 expression was increased after T cell receptor engagement and played a specific role in the polarization of CD4+ T cells towards pathogenic T helper-1 (Th1) cells producing interferon-γ (IFN-γ) and granulocyte monocyte colony stimulating factor (GM-CSF). Consequently, Foxo3-deficient mice exhibited reduced susceptibility to experimental autoimmune encephalomyelitis. At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+ T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+ T cells restored both IFN-γ and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.

Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus

“…ICU patients with more severe pneumonia showed correlated higher percentage of GM-CSF + and IL-6 + CD4 + T cells (Fig.2a, c). Pathogenic Th1 cells with both IFN-γ and GM-CSF expression have been reported in central nervous system inflammation 25 . Importantly, aberrant pathogenic Th1 cells with co-expressing IFNγ and GM-CSF exist only in ICU patients infected 2019-nCoV, whereas little was found in non-ICU patients and healthy controls, indicating this pathogenic Th1 cells which have correlative evidence from patients with severe disease, play a critical role for hyper-inflammatory responses in 2019-nCoV pathogenesis (Fig.2b, d).…”

Neurological manifestations of COVID-19: A systematic review

“…An activated systemic immune response might ultimately also lead to fatal encephalopathy or chronic CNS demyelination associated with long-term sequelae, depending on viral and host factors that may in uence disease severity. [17] T-helper 1 cells producing IFN-γ and GM-CSF, previously reported in CNS neuroin ammation [20], have also been found in COVID-19 patients in intensive care units [54]. Furthermore, accumulating evidence suggests that severely affected COVID-19 patients might suffer from a cytokine storm syndrome, which has been implicated as the putative mechanism underlying a case of COVID-19 associated with acute necrotizing encephalopathy [55].…”

“…Notably, not all neurological symptoms or complications require direct infection of cells or structures of the nervous system. Indirect neurotoxicity may result secondary to immune-mediated pathogenesis [2,20,21], coagulation dysfunction [22], cardiovascular comorbidities like hypertension or diabetes [23], altered glucose and lipid metabolism [24,25], disturbances in the lung-brain cross talk such as hypoxic encephalopathy [26], or as a consequence of an imbalanced gut-brain axis through disturbances of the gut microbiome during gastrointestinal SARS-CoV-2 infection [27] (Fig. 2b).…”

Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation

“…FOXO3 is a transcription factor belonging to the O subclass of the forkhead family. It is thought to be associated with tumorigenesis, immunoregulation, and even longevity of humans [41][42][43][44][45] . Besides, researchers discovered that FOXO3 regulates neurogenesis in adult by interacting with ten-eleven translocation-2 protein 46 and maintains redox balance in neural stem cells coordinating metabolic pathways 47 .…”