T follicular helper cells (T_FH): From physiological to pathological aging

The fraction that the elderly represent in the world's population is growing rapidly; numerous alterations that impact all organs and systems, including the immune system, are related to aging. A complex process common in the elderly, known as immunosenescence, is characterized by a decreased ability to respond to vaccination as well as an increased risk of bacterial and viral infections, autoimmune, cardiovascular and neurodegenerative diseases. These processes are associated with alterations in the innate and adaptive immune system and lead to a condition of chronic low-grade inflammation, referred to as inflammaging. However, the mechanisms underlying these processes are still unclear. Several types of immune cells are involved in this condition, including CD4⁺T cells subsets. T follicular helper (T_FH) cells and T follicular regulatory cells (T_FR) can be found in peripheral blood and lymphoid organs and are involved in maintaining immune homeostasis by regulating antibody production by B cells. Age-related changes in T_FH cells phenotype and function have been observed in both aging humans and mouse models. Cardiovascular and neurodegenerative diseases, prevalent in elderly subjects, are associated with dysfunctional T_FH cells and an altered T_FH/T_FR ratio. This review discusses the cellular and molecular alterations in T_FH cells and in their ratio to T_FR cells that occur with age, along with recent findings suggesting a possible link between T_FH cells and/or their subsets and cardiovascular and neurodegenerative diseases.