Yazar "Cui, Ye" seçeneğine göre listele

Listeleniyor 1 - 2 / 2
  • Küçük Resim Yok
    Öğe
    Combined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1
    (Mosby-Elsevier, 2020) Cui, Ye; Keles, Sevgi; Charbonnier, Louis-Marie; Jule, Amelie M.; Henderson, Lauren; Celik, Seyma Celikbilek; Reisli, Ismail
    Background: Mutations affecting DNA polymerases have been implicated in genomic instability and cancer development, but the mechanisms by which they can affect the immune system remain largely unexplored. Objective: We sought to establish the role of DNA polymerase M catalytic subunit (POLD1) as the cause of a primary immunodeficiency in an extended kindred. Methods: We performed whole-exome and targeted gene sequencing, lymphocyte characterization, molecular and functional analyses of the DNA polymerase delta (Pol delta) complex, and T- and B-cell antigen receptor repertoire analysis. Results: We identified a missense mutation (c. 3178C>T; p.R1060C) in POLD1 in 3 related subjects who presented with recurrent, especially herpetic, infections and T-cell lymphopenia with impaired T-cell but not B-cell proliferation. The mutation destabilizes the Pol delta complex, leading to ineffective recruitment of replication factor C to initiate DNA replication. Molecular dynamics simulation revealed that the R1060C mutation disrupts the intramolecular interaction between the POLD1 CysB motif and the catalytic domain and also between POLD1 and the Pol delta subunit POLD2. The patients exhibited decreased numbers of naive CD4 and especially CD8 T cells in favor of effector memory subpopulations. This skewing was associated with oligoclonality and restricted T-cell receptor beta-chain V-J pairing in CD8(+) but not CD4(+) T cells, suggesting that POLDR1060C differentially affects peripheral CD8(+) T-cell expansion and possibly thymic selection. Conclusion: These results identify gene defects in POLD1 as a novel cause of T-cell immunodeficiency.
  • Küçük Resim Yok
    Öğe
    A Stk4-Foxp3-NF-?B p65 transcriptional complex promotes Treg cell activation and homeostasis
    (Amer Assoc Advancement Science, 2022) Cui, Ye; Benamar, Mehdi; Schmitz-Abe, Klaus; Poondi-Krishnan, Varsha; Chen, Qian; Jugder, Bat-Erdene; Fatou, Benoit
    The molecular programs involved in regulatory T (T-reg) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in T-reg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4-NF-kappa B p65-Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in T-reg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-kappa B p65-Foxp3 complex formation, and defective Treg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient T-reg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes T-reg cellmediated immune tolerance.