TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation

Yunhan Ma; Yan Yang; Helong Dai; Changxiu Yan; Shengnan Yu; Shuaishuai Zhang; Zeyang Lin; Jinfeng Chen; Gaoyi Yu; Jing Zhang; Ping Yin; Jianhong Lu; Chunyan Shi; Zhijian Ye; Qingguo Ruan; Zhongquan Qi; Guohong Zhuang

doi:10.1016/j.clim.2023.109636

TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation

Clin Immunol. 2023 Jul:252:109636. doi: 10.1016/j.clim.2023.109636. Epub 2023 May 5.

Authors

Yunhan Ma¹, Yan Yang², Helong Dai³, Changxiu Yan², Shengnan Yu², Shuaishuai Zhang², Zeyang Lin⁴, Jinfeng Chen⁵, Gaoyi Yu², Jing Zhang⁶, Ping Yin⁴, Jianhong Lu², Chunyan Shi⁷, Zhijian Ye⁸, Qingguo Ruan⁹, Zhongquan Qi¹⁰, Guohong Zhuang¹¹

Affiliations

¹ Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen 361102, China; School of Medicine, Jiangsu University, Zhenjiang 212000, China.
² Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen 361102, China.
³ Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha 410000, China.
⁴ Department of Pathology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361001, China.
⁵ Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
⁶ Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University and Assistant Professor of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361000, China.
⁷ The Department of Oncology, Jiujiang No.1 People's Hospital, Jiujiang 332000, China.
⁸ Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen 361000, China.
⁹ Eye Institute of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao 266071, China. Electronic address: ruanqingguo@sdfmu.edu.cn.
¹⁰ Wuzhou Workers' Hospital, Wuzhou 543000, China; School of Medicine, Xiamen University, Xiamen 361102, China. Electronic address: yxyyz@gxu.edu.cn.
¹¹ Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen 361102, China. Electronic address: zhgh@xmu.edu.cn.

PMID: 37150242
DOI: 10.1016/j.clim.2023.109636

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.

Keywords: DCs; Heart transplantation; PI3K/AKT; TIPE2(−/−); Treg.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Dendritic Cells
Graft Rejection
Graft Survival
Heart Transplantation*
Intracellular Signaling Peptides and Proteins / genetics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases / metabolism
T-Lymphocytes, Regulatory*

Substances

Phosphatidylinositol 3-Kinases
TIPE2 protein, mouse
Intracellular Signaling Peptides and Proteins