The metabolic hormone leptin promotes the function of T(FH) cells and supports vaccine responses

Follicular helper T (T(FH)) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate T(FH) function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying T(FH) 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 T(FH) differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs T(FH) 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 T(FH) cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.