Conservative sequences in 3′UTR of TCRζ mRNA regulate TCRζ in SLE T cells

Tsuzaka, Kensei; Itami, Y; Kumazawa, Chika; Suzuki, Miyuki; Setoyama, Yumiko; Yoshimoto, Keiko; Suzuki, Katsuya; Abe, Tohru; Takeuchi, Tsutomu

doi:10.1016/j.bbrc.2007.12.145

Cited by 5 publications

(3 citation statements)

References 27 publications

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“…These data are consistent with the findings that (1) mutations in the zeta gene are relevant to the onset of the disease in some patients [21, 27–29] and (2) a mutation in ITAM of TCR zeta causes autoimmunity in mice, and T cells from such mice produced more IFN- γ than wild-type T cells [30]. It is known that the function of TCR is negatively regulated by CTLA-4, which downregulates activated TCR through association with phosphorylated TCR zeta [31, 32].…”

Section: Discussionsupporting

confidence: 92%

Reduced Expression of TCR Zeta Is Involved in the Abnormal Production of Cytokines by Peripheral T Cells of Patients with Systemic Lupus Erythematosus

Yoshimoto

Setoyama

Tsuzaka

et al. 2010

Journal of Biomedicine and Biotechnology

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Accumulating evidence suggests that dysfunction of T cells underlies the pathogenesis of systemic lupus erythematosus (SLE). We revealed that SLE T cells produced an abnormally excessive amount of IFN-γin vitro upon stimulation through TCR, and the expression level of TCR zeta was significantly reduced. The production of IFN-γ by SLE T cells was negatively correlated with the expression level of TCR zeta. This correlation was abolished when the cells were stimulated with TPA and ionomycin, which bypass TCR and introduce signals directly into the cells, but the production of IFN-γ by SLE T cells remained abnormally elevated. Taken together, these data suggest that regulatory mechanisms not only for the expression of TCR zeta but also for the production of IFN-γ were impaired in SLE T cells. These impairments may be responsible for the aberrant responses of SLE T cells and partly involved in the development of SLE.

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Section: Discussionsupporting

confidence: 92%

Reduced Expression of TCR Zeta Is Involved in the Abnormal Production of Cytokines by Peripheral T Cells of Patients with Systemic Lupus Erythematosus

Yoshimoto

Setoyama

Tsuzaka

et al. 2010

Journal of Biomedicine and Biotechnology

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“…Patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) (39), Hashimoto's thyroiditis (HT) (43), giant cell arteritis (GCA) (44), relapsing-remitting multiple sclerosis (RRMS) (45) and coeliac disease (CD) (46) showed upregulated FOXP3DE2 isoforms in peripheral blood mononuclear cells (PBMCs) compared to control subjects. On the other hand, patients with rheumatoid arthritis (RA) (47), systemic lupus erythematosus (SLE) (47,48), inflammatory bowel diseases (IBD) (29), myelodysplastic syndromes (MDS) (49) and RRMS (50) showed lower or normal FOXP3DE2 isoform levels. The inconsistent results shown in the studies investigating the same disease might be partly due to the differences in the disease stages and the detection methods.…”

Section: Changes Of Foxp3fl and Foxp3de2 Isoforms In Autoimmune And I...mentioning

confidence: 99%

Metabolic regulation of forkhead box P3 alternative splicing isoforms and their impact on health and disease

Luo,

Zhang,

Saleh

et al. 2023

Front. Immunol.

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Forkhead Box P3 (FOXP3) is crucial for the development and suppressive function of human regulatory T cells (Tregs). There are two predominant FOXP3 splicing isoforms in healthy humans, the full-length isoform and the isoform lacking exon 2, with different functions and regulation mechanisms. FOXP3 splicing isoforms show distinct abilities in the cofactor interaction and the nuclear translocation, resulting in different effects on the differentiation, cytokine secretion, suppressive function, linage stability, and environmental adaptation of Tregs. The balance of FOXP3 splicing isoforms is related to autoimmune diseases, inflammatory diseases, and cancers. In response to environmental challenges, FOXP3 transcription and splicing can be finely regulated by T cell antigen receptor stimulation, glycolysis, fatty acid oxidation, and reactive oxygen species, with various signaling pathways involved. Strategies targeting energy metabolism and FOXP3 splicing isoforms in Tregs may provide potential new approaches for the treatment of autoimmune diseases, inflammatory diseases, and cancers. In this review, we summarize recent discoveries about the FOXP3 splicing isoforms and address the metabolic regulation and specific functions of FOXP3 splicing isoforms in Tregs.

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“…16 As a consequence, transcript stability and translation of this isoform are significantly lower than the isoform generated in the presence of normal levels of ASF/SF2. 17,18 Finally, increased Caspase 3 activity in SLE T cells has been associated with enhanced proteolysis of CD3ζ. In concordance, treatment with the small molecule DEVD, a Caspase 3 inhibitor, restores CD3ζ levels in SLE T cells.…”

Section: Tcr Signaling In Sle T Cellsmentioning

confidence: 99%