Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion

Summary: Exhausted CD8+ T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+ T cell exhaustion, but it remains unclear whet...

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Main Authors: Kaili Ma, Lina Sun, Mingjing Shen, Xin Zhang, Zhen Xiao, Jiajia Wang, Xiaowei Liu, Kanqiu Jiang, F. Xiao-Feng Qin, Feng Guo, Baojun Zhang, Lianjun Zhang
Format: Article
Language:English
Published: Elsevier 2022-05-01
Series:iScience
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Online Access:http://www.sciencedirect.com/science/article/pii/S2589004222006186
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author Kaili Ma
Lina Sun
Mingjing Shen
Xin Zhang
Zhen Xiao
Jiajia Wang
Xiaowei Liu
Kanqiu Jiang
F. Xiao-Feng Qin
Feng Guo
Baojun Zhang
Lianjun Zhang
author_facet Kaili Ma
Lina Sun
Mingjing Shen
Xin Zhang
Zhen Xiao
Jiajia Wang
Xiaowei Liu
Kanqiu Jiang
F. Xiao-Feng Qin
Feng Guo
Baojun Zhang
Lianjun Zhang
author_sort Kaili Ma
collection DOAJ
description Summary: Exhausted CD8+ T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+ T cell exhaustion, but it remains unclear whether the increased CD38 directly promotes T cell dysfunctionality. Here, we surprisingly found that although Cd38 deficiency partially reverses NAD+ degradation and T cell dysfunction in vitro, the terminal exhausted differentiation of adoptively transferred CD8+ T cells in tumor is not impacted by either deficiency or overexpression of CD38. Monitoring the dynamic NAD+ levels shows that NAD+ levels are comparable between tumor infiltrated WT and Cd38−/− CD8+ T cells. Therefore, our results suggest that decreased NAD+ are correlated with T cell dysfunction, but deficiency of CD38 is not enough for rescuing NAD+ in tumor infiltrated CD8+ T cells and fails to increase the efficacy of antitumor T cell therapy.
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spelling doaj.art-95851dc10bb64e0bb9cf11c80aab74812022-12-22T00:30:20ZengElsevieriScience2589-00422022-05-01255104347Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustionKaili Ma0Lina Sun1Mingjing Shen2Xin Zhang3Zhen Xiao4Jiajia Wang5Xiaowei Liu6Kanqiu Jiang7F. Xiao-Feng Qin8Feng Guo9Baojun Zhang10Lianjun Zhang11CAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, ChinaDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, ChinaDepartment of Thoracic and Cardiac Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, ChinaCAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu 211198, ChinaCAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, ChinaCAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; School of Engineering, China Pharmaceutical University, Nanjing, Jiangsu 211198, ChinaCAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, ChinaDepartment of Thoracic and Cardiac Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, ChinaCAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, ChinaDepartment of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China; Corresponding authorDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China; Corresponding authorCAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Corresponding authorSummary: Exhausted CD8+ T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+ T cell exhaustion, but it remains unclear whether the increased CD38 directly promotes T cell dysfunctionality. Here, we surprisingly found that although Cd38 deficiency partially reverses NAD+ degradation and T cell dysfunction in vitro, the terminal exhausted differentiation of adoptively transferred CD8+ T cells in tumor is not impacted by either deficiency or overexpression of CD38. Monitoring the dynamic NAD+ levels shows that NAD+ levels are comparable between tumor infiltrated WT and Cd38−/− CD8+ T cells. Therefore, our results suggest that decreased NAD+ are correlated with T cell dysfunction, but deficiency of CD38 is not enough for rescuing NAD+ in tumor infiltrated CD8+ T cells and fails to increase the efficacy of antitumor T cell therapy.http://www.sciencedirect.com/science/article/pii/S2589004222006186ImmunologyCell biologyCancer
spellingShingle Kaili Ma
Lina Sun
Mingjing Shen
Xin Zhang
Zhen Xiao
Jiajia Wang
Xiaowei Liu
Kanqiu Jiang
F. Xiao-Feng Qin
Feng Guo
Baojun Zhang
Lianjun Zhang
Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
iScience
Immunology
Cell biology
Cancer
title Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
title_full Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
title_fullStr Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
title_full_unstemmed Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
title_short Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
title_sort functional assessment of the cell autonomous role of nadase cd38 in regulating cd8 t cell exhaustion
topic Immunology
Cell biology
Cancer
url http://www.sciencedirect.com/science/article/pii/S2589004222006186
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