Abstract

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

T follicular helper (TFH) cell numbers are increased after vaccination and fewer of these cells might result in reduced vaccine responses. Here the authors show in mice and humans that leptin promotes TFH differentiation and that low leptin levels can impair TFH response to vaccines and virus protection in mice.

Details

Title
The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses
Author
Deng, Jun 1   VIAFID ORCID Logo  ; Chen, Qian 2 ; Chen, Zhian 3 ; Liang Kaili 4 ; Gao, Xin 5 ; Wang, Xiaohui 6 ; Makota Fadzai V 7 ; Ong, Hong Sheng 7 ; Wan Yanmin 8 ; Luo Kaiming 4   VIAFID ORCID Logo  ; Gong Dongcheng 4 ; Yu, Xiang 9 ; Camuglia Sarina 10 ; Zeng Qunxiong 4 ; Zhou, Tao 11 ; Xue, Feng 11 ; He, Jing 12   VIAFID ORCID Logo  ; Wei Yunbo 13 ; Fan, Xiao 6 ; Ma Jianyang 14 ; Hill, Danika L 15 ; Pierson, Wim 15 ; Nguyen Thi H O 16   VIAFID ORCID Logo  ; Zhou, Haibo 9 ; Wang, Yan 9 ; Shen, Wei 17 ; Sun, Lingyun 18 ; Li, Zhanguo 12   VIAFID ORCID Logo  ; Xia Qiang 11 ; Qian Kun 19   VIAFID ORCID Logo  ; Ye Lilin 20 ; Rockman, Steven 21 ; Linterman, Michelle A 15   VIAFID ORCID Logo  ; Kedzierska, Katherine 16   VIAFID ORCID Logo  ; Shen, Nan 22   VIAFID ORCID Logo  ; Lu, Liwei 23   VIAFID ORCID Logo  ; Yu, Di 24   VIAFID ORCID Logo 

1  Shanghai Jiao Tong University School of Medicine, China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); The University of Hong Kong, Department of Pathology and Shenzhen Institute of Research and Innovation, Hong Kong, China (GRID:grid.194645.b) (ISNI:0000000121742757); Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
2  The University of Hong Kong, Department of Pathology and Shenzhen Institute of Research and Innovation, Hong Kong, China (GRID:grid.194645.b) (ISNI:0000000121742757); Shanghai Jiao Tong University School of Medicine, Department of Ophthalmology, Shanghai General Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
3  Australian National University, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra, Australia (GRID:grid.1001.0) (ISNI:0000 0001 2180 7477); The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
4  Shanghai Jiao Tong University School of Medicine, China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
5  Shanghai Jiao Tong University School of Medicine, China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Australian National University, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra, Australia (GRID:grid.1001.0) (ISNI:0000 0001 2180 7477) 
6  The University of Hong Kong, Department of Pathology and Shenzhen Institute of Research and Innovation, Hong Kong, China (GRID:grid.194645.b) (ISNI:0000000121742757) 
7  Australian National University, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra, Australia (GRID:grid.1001.0) (ISNI:0000 0001 2180 7477) 
8  Fudan University, Department of Infectious Diseases, Huashan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Fudan University, Department of Radiology, Shanghai Public Health Clinical Center, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
9  Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
10  Seqirus, Parkville, Australia (GRID:grid.16821.3c) 
11  Shanghai Jiao Tong University School of Medicine, Department of Liver Surgery, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
12  Peking University People’s Hospital, Department of Rheumatology and Immunology, Beijing, China (GRID:grid.411634.5) (ISNI:0000 0004 0632 4559) 
13  Qilu University of Technology (Shandong Academy of Sciences), Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Jinan, China (GRID:grid.443420.5) (ISNI:0000 0000 9755 8940) 
14  Shanghai Jiao Tong University School of Medicine, China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
15  Babraham Institute, Lymphocyte Signaling and Development, Cambridge, UK (GRID:grid.418195.0) (ISNI:0000 0001 0694 2777) 
16  University of Melbourne, Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
17  Shanghai Jiao Tong University School of Medicine, Department of Laboratory Medicine, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
18  The Affiliated Drum Tower Hospital of Nanjing University Medical School, Department of Rheumatology and Immunology, Nanjing, China (GRID:grid.428392.6) (ISNI:0000 0004 1800 1685) 
19  Shanghai Jiao Tong University, School of Biomedical Engineering, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
20  Third Military Medical University, Institute of Immunology, Chongqing, China (GRID:grid.410570.7) (ISNI:0000 0004 1760 6682); Chongqing International Institute for Immunology, Chongqing, China (GRID:grid.410570.7) 
21  Seqirus, Parkville, Australia (GRID:grid.410570.7) 
22  Shanghai Jiao Tong University School of Medicine, China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
23  The University of Hong Kong, Department of Pathology and Shenzhen Institute of Research and Innovation, Hong Kong, China (GRID:grid.194645.b) (ISNI:0000000121742757); Chongqing International Institute for Immunology, Chongqing, China (GRID:grid.194645.b) 
24  Shanghai Jiao Tong University School of Medicine, China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Australian National University, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra, Australia (GRID:grid.1001.0) (ISNI:0000 0001 2180 7477); The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); Qilu University of Technology (Shandong Academy of Sciences), Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Jinan, China (GRID:grid.443420.5) (ISNI:0000 0000 9755 8940) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-23220-x
ProQuest document ID
2531420554
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.