Impaired HA-specific T follicular helper cell and antibody responses to influenza vaccination are linked to inflammation in humans

Antibody production following vaccination can provide protective immunity to subsequent infection from pathogens such as influenza. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at risk groups. Here, by studying the breadth of anti-hemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper cells (cTfh) cells are the best predictor of high titre antibody responses. Using MHC class II tetramers we demonstrate that HA-specific cTfh cells can derived from pre-existing memory CD4⁺T cells and have a diverse TCR repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together this suggests that strategies that temporarily dampen inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.