Dataset Information

Dysfunctional immunoregulation in human liver allograft rejection associated with compromised galectin-1/CD7 pathway function.

ABSTRACT: Regulatory T cells in rejected allograft patients display an inability to control responder T cells. Galectin-1 (Gal1) inhibits responder T cells through binding CD7. We investigated whether the dysfunctional immunoregulation in liver allograft rejection patients results from reduced regulatory T-cell Gal1 expression and/or responder T-cell CD7 expression. Circulating regulatory T cells and responder T cells were profiled from 31 acute rejection transplant patients, 85 transplant patients in remission, and 40 healthy controls. CD7+ and CD7- responder T cells were co-cultured with regulatory T cells to assess regulatory T-cell suppressor function. Gal1-small interfering RNA was used to silence regulatory T-cell Gal1. The CD7+ cell percentage was inversely correlated with AST, ALT, and GGT levels. The proportions of CD7+ responder T cells and Gal1+ regulatory T cells were higher in healthy controls than in transplant patients in remission and lowest in acute rejection transplant patients. Notably, CD7+ responder T-cell susceptibility to Gal1+ regulatory T-cell control was ranked in the same manner. Silencing Gal1 expression in regulatory T cells reduced their ability to suppress CD7+ (but not CD7-) responder T cells. Additionally, the proportions of CD43+ and CD45+ responder T cells were higher in healthy controls than in acute rejection transplant patients. CD43 co-expression (but not CD45 co-expression) on CD7+ responder T cells promoted their apoptosis in a Gal1-dependent manner. In sum, dysfunctional immunoregulation in liver allograft rejection patients can be partly attributed to reduced regulatory T-cell Gal1 expression and reduced responder T-cell CD7 expression. Responder T-cell CD43 downregulation in acute rejection patients may further contribute to reduced responder T-cell responsiveness to regulatory T-cell control.

SUBMITTER: Wei S

PROVIDER: S-EPMC5833641 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Dysfunctional immunoregulation in human liver allograft rejection associated with compromised galectin-1/CD7 pathway function.

Wei Sidong S Cao Ding D Liu Zuojin Z Li Jinheng J Wu Hao H Gong Jianping J Liu Yiming Y Wu Yakun Y

Cell death & disease 20180220 3

Regulatory T cells in rejected allograft patients display an inability to control responder T cells. Galectin-1 (Gal1) inhibits responder T cells through binding CD7. We investigated whether the dysfunctional immunoregulation in liver allograft rejection patients results from reduced regulatory T-cell Gal1 expression and/or responder T-cell CD7 expression. Circulating regulatory T cells and responder T cells were profiled from 31 acute rejection transplant patients, 85 transplant patients in rem ...[more]

PMID: 29463785

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Project description:The IL-7/IL-7R pathway is essential for lymphocyte development and disturbances in the pathway can lead to immune deficiency or T cell mediated destruction. Here, the effect of transient hyperexpression of IL-7 was investigated on immune regulation and allograft rejection under immunosuppression. An experimental in vivo immunosuppressive mouse model of IL-7 hyperexpression was developed using transgenic mice (C57BL/6 background) carrying a tetracycline inducible IL-7 expression cassette, which allowed the temporally controlled induction of IL-7 hyperexpression by Dexamethasone and Doxycycline treatment. Upon induction of IL-7, the B220+ c-kit+ Pro/Pre-B I compartment in the bone marrow increased as compared to control mice in a serum IL-7 concentration-correlated manner. IL-7 hyperexpression also preferentially increased the population size of memory CD8+ T cells in secondary lymphoid organs, and reduced the proportion of CD4+Foxp3+ T regulatory cells. Of relevance to disease, conventional CD4+ T cells from an IL-7-rich milieu escaped T regulatory cell-mediated suppression in vitro and in a model of autoimmune diabetes in vivo. These findings were validated using an IL-7/anti-IL7 complex treatment mouse model to create an IL-7 rich environment. To study the effect of IL-7 on islet graft survival in a mismatched allograft model, BALB/c mice were rendered diabetic by streptozotocin und transplanted with IL-7-inducible or control islets from C57BL/6 mice. As expected, Dexamethasone and Doxycycline treatment prolonged graft median survival as compared to the untreated control group in this transplantation mouse model. However, upon induction of local IL-7 hyperexpression in the transplanted islets, graft survival time was decreased and this was accompanied by an increased CD4+ and CD8+ T cell infiltration in the islets. Altogether, the findings show that transient elevations of IL-7 can impair immune regulation and lead to graft loss also under immune suppression.

Dataset Information

Dysfunctional immunoregulation in human liver allograft rejection associated with compromised galectin-1/CD7 pathway function.

Publications

Dysfunctional immunoregulation in human liver allograft rejection associated with compromised galectin-1/CD7 pathway function.

Similar Datasets

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