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.
Highlights
Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation
We show that low levels of serum leptin in both young and elderly healthy groups are associated with reduced antibody responses to influenza and hepatitis B virus (HBV) vaccines
Using the Chromatin Immunoprecipitation (ChIP) assay, we found that leptin increased the binding of Stat[3] to the Il21 promoter in mouse CD4+ T cells (Fig. 5d, raw gel blots in Source Data), suggesting that the leptin-Stat[3] axis enhances the Il21 transcription
Summary
Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. 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. Studies suggest that aberrant TFH generation in autoimmune disease is likely driven by continuous (auto)antigen stimulation and the upregulation of TFH-inducing cytokines, such as IL-65–8 Between these two extreme ends of the spectrum of TFH cell function, we know very little about how the function of TFH cells is regulated in the general population. We show that low levels of serum leptin in both young and elderly healthy groups are associated with reduced antibody responses to influenza and hepatitis B virus (HBV) vaccines. Leptin promotes the differentiation and function of both human and mouse TFH cells in culture and is required to support TFH function and effective humoral immunity to infection, immunisation and vaccination in mice. Our results suggest leptin is a physiological regulator of TFH function and insufficient leptin might serve as a biomarker to identify the risk for low vaccine efficacy
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