The emerging role of T follicular helper (TFH) cells in aging: Influence on the immune frailty

The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (T_FH) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of T_FH cells have been identified in humans and mice and modifications in T_FH cell phenotype and function progressively occur with age. Dysfunctional T_FH cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (T_FR) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to T_FH cells in regulating immunity. Indeed, changes in T_FH/T_FR cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both T_FH cells and T_FR cells that occur in aging and recent findings suggesting that T_FH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.