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CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival

A transplanted organ is always rejected in the absence of any immunosuppressive treatment due to vigorous alloimmunity. However, continuously global immunosuppression with a conventional immunosuppressant may result in severe side effects, including nephrotoxicity, tumors and infections. Tregs have...

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Autores principales: Liu, Huazhen, Qiu, Feifei, Wang, Yuanzhong, Zeng, Qiaohuang, Liu, Cuihua, Chen, Yuchao, Liang, Chun-Ling, Zhang, Qunfang, Han, Ling, Dai, Zhenhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399415/
https://www.ncbi.nlm.nih.gov/pubmed/30863408
http://dx.doi.org/10.3389/fimmu.2019.00306
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author Liu, Huazhen
Qiu, Feifei
Wang, Yuanzhong
Zeng, Qiaohuang
Liu, Cuihua
Chen, Yuchao
Liang, Chun-Ling
Zhang, Qunfang
Han, Ling
Dai, Zhenhua
author_facet Liu, Huazhen
Qiu, Feifei
Wang, Yuanzhong
Zeng, Qiaohuang
Liu, Cuihua
Chen, Yuchao
Liang, Chun-Ling
Zhang, Qunfang
Han, Ling
Dai, Zhenhua
author_sort Liu, Huazhen
collection PubMed
description A transplanted organ is always rejected in the absence of any immunosuppressive treatment due to vigorous alloimmunity. However, continuously global immunosuppression with a conventional immunosuppressant may result in severe side effects, including nephrotoxicity, tumors and infections. Tregs have been widely used to inhibit allograft rejection, especially in animal models. However, it's well accepted that administration of Tregs alone is not satisfactory in immune-competent wild-type animals. Therefore, it's imperative to promote Treg therapies under the cover of other approaches, including costimulatory blockade. In the present study, we demonstrated that administration of in vitro-expanded CD8(+)CD122(+)PD-1(+) Tregs synergized with costimulatory blockade of CD40/CD154, but not B7/CD28, to prolong skin allograft survival in wild-type mice and to reduce cellular infiltration in skin allografts as well. Treg treatment and blockade of CD40/CD154, but not B7/CD28, also exhibited an additive effect on suppression of T cell proliferation in vitro and pro-inflammatory cytokine expression in skin allografts. Importantly, blocking B7/CD28, but not CD40/CD154, costimulation decreased the number of transferred CD8(+)CD122(+)PD-1(+) Tregs and their expression of IL-10 in recipient mice. Furthermore, it's B7/CD28, but not CD40/CD154, costimulatory blockade that dramatically reduced IL-10 production by CD8(+)CD122(+)PD-1(+) Tregs in vitro, suggesting that B7/CD28, but not CD40/CD154, costimulation is critical for their production of IL-10. Indeed, infusion of IL-10-deficient CD8(+)CD122(+)PD-1(+) Tregs failed to synergize with anti-CD154 Ab treatment to further prolong allograft survival. Our data may explain why blocking B7/CD28 costimulatory pathway does not boost IL-10-dependent Treg suppression of alloimmunity. Thus, these findings could be implicated in clinical organ transplantation.
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spelling pubmed-63994152019-03-12 CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival Liu, Huazhen Qiu, Feifei Wang, Yuanzhong Zeng, Qiaohuang Liu, Cuihua Chen, Yuchao Liang, Chun-Ling Zhang, Qunfang Han, Ling Dai, Zhenhua Front Immunol Immunology A transplanted organ is always rejected in the absence of any immunosuppressive treatment due to vigorous alloimmunity. However, continuously global immunosuppression with a conventional immunosuppressant may result in severe side effects, including nephrotoxicity, tumors and infections. Tregs have been widely used to inhibit allograft rejection, especially in animal models. However, it's well accepted that administration of Tregs alone is not satisfactory in immune-competent wild-type animals. Therefore, it's imperative to promote Treg therapies under the cover of other approaches, including costimulatory blockade. In the present study, we demonstrated that administration of in vitro-expanded CD8(+)CD122(+)PD-1(+) Tregs synergized with costimulatory blockade of CD40/CD154, but not B7/CD28, to prolong skin allograft survival in wild-type mice and to reduce cellular infiltration in skin allografts as well. Treg treatment and blockade of CD40/CD154, but not B7/CD28, also exhibited an additive effect on suppression of T cell proliferation in vitro and pro-inflammatory cytokine expression in skin allografts. Importantly, blocking B7/CD28, but not CD40/CD154, costimulation decreased the number of transferred CD8(+)CD122(+)PD-1(+) Tregs and their expression of IL-10 in recipient mice. Furthermore, it's B7/CD28, but not CD40/CD154, costimulatory blockade that dramatically reduced IL-10 production by CD8(+)CD122(+)PD-1(+) Tregs in vitro, suggesting that B7/CD28, but not CD40/CD154, costimulation is critical for their production of IL-10. Indeed, infusion of IL-10-deficient CD8(+)CD122(+)PD-1(+) Tregs failed to synergize with anti-CD154 Ab treatment to further prolong allograft survival. Our data may explain why blocking B7/CD28 costimulatory pathway does not boost IL-10-dependent Treg suppression of alloimmunity. Thus, these findings could be implicated in clinical organ transplantation. Frontiers Media S.A. 2019-02-26 /pmc/articles/PMC6399415/ /pubmed/30863408 http://dx.doi.org/10.3389/fimmu.2019.00306 Text en Copyright © 2019 Liu, Qiu, Wang, Zeng, Liu, Chen, Liang, Zhang, Han and Dai. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Liu, Huazhen
Qiu, Feifei
Wang, Yuanzhong
Zeng, Qiaohuang
Liu, Cuihua
Chen, Yuchao
Liang, Chun-Ling
Zhang, Qunfang
Han, Ling
Dai, Zhenhua
CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival
title CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival
title_full CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival
title_fullStr CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival
title_full_unstemmed CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival
title_short CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival
title_sort cd8+cd122+pd-1+ tregs synergize with costimulatory blockade of cd40/cd154, but not b7/cd28, to prolong murine allograft survival
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399415/
https://www.ncbi.nlm.nih.gov/pubmed/30863408
http://dx.doi.org/10.3389/fimmu.2019.00306
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