One of the key parts of the adaptive immune system for generating protective immunity and immunological memory is the germinal centre response. The germinal centre is a specialised microenviroment formed in secondary lymphoid tissues after infection or immunization. The germinal centre produces memory B cells and somatically-mutated antibody-secreting plasma cells that provide prolonged protection throughout life. The formation, maintenance and selection of germinal centre B cells are absolutely dependent on T cell help.
T follicular helper cells (Tfh) are a specialised subset of CD4+ helper T cells that provide growth and differentiation signals to germinal centre B cells. Tfh cells mediate positive selection of high-affinity B cell clones in the germinal centre, and thereby determine which B cells exit the germinal centre as plasma cells and memory B cells which provide life-long protection against future infections. In addition to Tfh cells, we and others described another subset of CD4+ T cells within the germinal centre, T follicular regulatory (Tfr) cells.
Tfr cells require similar differentiation cues to Tfh cells and share some phenotypic charateristics, however, they derive from suppressive Foxp3+ regulatory T cells, and have suppressive function. Tfr cells act as regulatory cells in the germinal centre, controlling the size and output of the response. Together, Tfh and Tfr cells control the initiation, size and output of the germinal centre, and are therefore critical players in generating life-long antibody-mediated immunity after vaccination.
Because of the central role of the germinal centre in generating immunological memory, a potent germinal centre response is critical for a successful response to vaccination. With advancing age, the size of the germinal centre response and the efficacy of vaccination diminish, and T cells are one of the primary contributors to this decline. Our research is focused on understanding the cellular and molecular changes that occur in T cells with age that contribute to the age-dependent decline in the germinal centre response.
Poor germinal centre responses in aged mice after immunisation. This image shows a section of inguinal lymph nodes taken 14 days after immunisation. In a 2 month old mouse (left) there is are large germinal centres (Blue Ki67 staining surrounded by yellow IgD staining) that contain T follicular helper T cells (green CD3 staining), these structures are smaller in 22 month old mice (right).