Requirement for POH1 in differentiation and maintenance of regulatory T cells

Abstract

Foxp3-expressing regulatory T (Treg) cells are essential for averting autoimmune diseases and maintaining immune homeostasis. However, the molecular mechanisms underlying the development and maintenance of Treg cells are still unclear. Here, we found that T cell-specific deletion of the gene encoding the deubiquitinase POH1 compromised the development of mature T cells, especially CD4Foxp3 Treg cells. Moreover, POH1 deficiency significantly attenuated the transition of CD25 Treg cell precursors into Foxp3 Treg cells accompanied by downregulation of interleukin 2 (IL-2)-STAT5 signaling. Deletion of POH1 in generated CD4Foxp3 Treg cells led to an early onset of fetal autoimmune disorders and a decrease in the pool size of peripheral Treg cells in mice, which were mostly due to decreased expansion of these cells. Thus, these results revealed that POH1 has a pivotal role in the development and maintenance of CD4Foxp3 Treg cells and contributes to immune tolerance.

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

“…The specific deletion of the deubiquitinase POH1 gene in T cells compromised the development of mature T cells, especially CD4 + Foxp3 + Tregs. Furthermore, POH1 deficiency significantly attenuated the transition of CD25 + Tregs precursors into Foxp3 + Tregs and was accompanied by downregulation of IL-2-STAT5 signalling [ 203 ]. Idelalisib is a highly selective PI3K (PI3Kδ) isoform-specific inhibitor effective in relapsed/refractory CLL and follicular lymphoma.…”

Cancer‐associated fibroblasts: Secretions, interactions, and therapy

“…M1 phenotype is a proinflammatory cell type known for having antitumor activity, while M2 phenotype is an immunosuppressive cell type responsible for tumor progression. 42,43 CAFs release a high amount of lactic acid to the TME. Beside creating an acidified milieu for tumor progression, these high lactate levels account for macrophage polarization toward an M2 phenotype 32,42,44,45 through which they promote multiple tumorigenic functions including tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT), and immune escape, invasion, stemness, and metastasis in cancer cells.…”

“…29,41 Hypoxia and related processes, as it has been understood from a number of reports, play critical roles in progression of cancer. 43,51,63 Responses from cancer cells to radiation therapy is also influenced from the rate of ECM tension within the TME. The rigidity induced by matrix cross-linking is suppressed by inhibition of TGF-β and p300 signal transductions.…”

“…Macrophages generally classified into the two extremes: classically activated M1 cells and alternatively activated M2 cells. M1 phenotype is a proinflammatory cell type known for having antitumor activity, while M2 phenotype is an immunosuppressive cell type responsible for tumor progression . CAFs release a high amount of lactic acid to the TME.…”

Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity

“…Differentiation of Tregs is tightly controlled by the transcription factor STAT5 [36], which has been shown to be positively regulated by the DUB POH1. Consistently, development of Tregs is severely impaired in T cell-specific POH1 knockout mice [37]. Furthermore, the immunosuppressive function of Tregs is negatively regulated by the Lys48-linked ubiquitination of Foxp3, which is mediated by the E3 ligase STUB1 [38].…”