1. TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation.
- Author
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Ma Y, Yang Y, Dai H, Yan C, Yu S, Zhang S, Lin Z, Chen J, Yu G, Zhang J, Yin P, Lu J, Shi C, Ye Z, Ruan Q, Qi Z, and Zhuang G
- Subjects
- Mice, Animals, Phosphatidylinositol 3-Kinases metabolism, Dendritic Cells, Mice, Inbred C57BL, Allografts, Mice, Inbred BALB C, Graft Survival, Graft Rejection, Intracellular Signaling Peptides and Proteins genetics, T-Lymphocytes, Regulatory, Heart Transplantation
- Abstract
It has been reported that deletion of tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2, TIPE2) facilitates the activation of T-cell receptors. However, the role of TIPE2 in T-cell-mediated acute transplant rejection remains unclear. To illustrate the underlying cellular mechanisms, we transplanted BALB/c hearts into C57BL/6 wild-type (WT) or C57BL/6 mice deficient for TIPE2 (TIPE2
-/- ) and found that TIPE2-/- recipient mice showed significantly prolonged survival of heart allografts and suppressed maturation of CD11c+ dendritic cells (DCs), which largely abolished the activation and proliferation of alloreactive T cells and their cytotoxic activity. TIPE2-/- DCs increased CD4+ CD25+ Foxp3+ CD127- regulatory T cells (Tregs)generation, likely by inhibiting DCs maturation and CD80 and CD86 expression. Administration of anti-CD25 abolished the allograft survival induced by TIPE2 deficiency. Moreover, TIPE2 deficiency increased IL-10 production in T cells and in recipient serum and allografts. Mechanistic studies revealed that TIPE2-/- restrained the maturation of DCs via inhibition of PI3K/AKT phosphorylation during alloantigen stimulation. Taken together, TIPE2 deficiency in recipient mice inhibited acute rejection by increasing Tregs generated by immature DCs. Thus, TIPE2 could be a therapeutic target for suppressing rejection in organ transplantation., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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