A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

Abstract

The NF-κB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4 and CD8 donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-γ and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20 T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20 T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD.

A20 Restrains Thymic Regulatory T Cell Development

“…1B, 1D , Supplemental Fig. 1B, 1C ), which is in line with previous observations ( 38 ). To exclude a bias of age on the development of T reg cells ( 43 ), we analyzed splenocytes of young (12-d-old) and adult (50-d-old) CD4 A20 +/+ and CD4 A20 −/− mice.…”

“…In vivo, neither proliferation nor apoptosis was significantly affected in A20-deficient T reg cells, contrary to A20 −/− effector T cells, which showed increased rates of apoptosis. This is in line with previous findings that show that A20 regulates cell death and survival of effector T cells ( 34 , 35 , 38 ). At the current stage, the molecular mechanisms to explain the relative insensitivity of A20 −/− T reg cells toward IL-2 remain unclear.…”

“…Mice with cell type–specific deficiency of A20 in T cells were generated by breeding A20 F/F mice ( 25 ) with CD4Cre transgenic mice ( 37 ) as previously described ( 38 ). C57BL/6 (H-2Kb, Thy-1.2) and BALB/c (H-2Kd, Thy-1.2) mice were purchased from Janvier Labs.…”

A20 deficiency in hematopoietic stem cells causes lymphopenia and myeloproliferation due to elevated Interferon-γ signals

“…Mice deficient for A20 exhibit hypersensitivity to TNF and premature death due to severe inflammation and cachexia 16 . Deletion of A20 in specific cells of the immune system, including B cells 17 , T cells 18 , dendritic cells 19 , and myeloid cells 20 resulted in a variety of multi-organ inflammation and immune pathologies 14 . Consistently, Mx1-Cre or ERT2-Cre mediated ablation of A20 in mice resulted in increased myeloid differentiation and rapid B cell apoptosis 21 .…”

Therapeutic efficacy of combined administration of thymosin and oxaliplatin in elderly gastric ulcer patients and its effect on cellular immunity and matrix metalloproteinase

“…Tiggio is a new type of fluorouracil-based chemotherapy which has achieved good results in the treatment of GC [2]. Thymosin, an immune potentiator, enhances the maturation and differentiation of T lymphocytes and also reduces the side effects of chemotherapy [3]. Therefore, in this study, the impact of combination treatment with thymosin, oxaliplatin and tiggio on aged GC sufferers was investigated with respect to cellular immunity, matrix metalloproteinase and endocrine function of tumors.…”