T follicular helper cell development and functionality in immune ageing

Abstract

By 2050, there will be over 1.6 billion adults aged 65 years and older, making age-related diseases and conditions a growing public health concern. One of the leading causes of death in the ageing population is pathogenic infections (e.g. influenza, Streptococcus pneumoniae). This age-dependent susceptibility to infection has been linked to a reduced ability of the ageing immune system to mount protective responses against infectious pathogens, as well as to vaccines against these pathogens. The primary immune response that promotes protection is the production of antibodies by B cells - a response that is directly mediated by T follicular helper (T_FH) cells within germinal centers (GCs) in secondary lymphoid tissues. In this review, we will summarize the current knowledge on the development and functionality of T_FH cells, the use of circulating T_FH (cT_FH) cells as vaccine biomarkers, and the influence of age on these processes. Moreover, we will discuss the strategies for overcoming T_FH cell dysfunction to improve protective antibody responses in the ageing human population.

Keywords: B cell antibody production; Immunosenescence; T cell differentiation; T follicular regulatory cell; germinal center; vaccine response.

Figure 1.. Alterations in T_FH cells during aging.

During a primary immune response, naïve CD4 T cells (Na) are recruited from the blood into the tissue, where they interaction with dendritic cells (DC). If activated via their T cell receptor in conjugation with the appropriate co-stimulation, naïve CD4 T cells upregulate CXCR5 and move into the B cell follicle. These precursor T_FH cells (pT_FH ) interact with local B cells to undergo full maturation into bona fide T_FH cells, which again interact with B cells within germinal centers. This germinal center interaction induces the production of high affinity antibodies as well as the release of activated memory T_FH cells (*T_FH ) from the tissue back into the blood. Memory T_FH cells in the blood can also be re-recruited into the follicle upon secondary exposure (i.e. memory recall) to rapidly promote the production of antibodies. T_FH responses can be inhibited by T follicular regulatory cells (T_FR) within follicles. During aging, multiple changes in this pathway occur, including alterations of naïve CD4 and T_FH cell frequencies within the blood, reductions in T_FH -B cell interactions and increases in T_FR cells - which in turn lead to lower production of antigen-specific antibodies and activated T_FH cells.

Figure 2.. Interventions for enhancing T_FH-mediated vaccine responses during aging.

Multiple steps in the development of T_FH responses with age are possible targets for therapeutic interventions. These targets include 1) altering the frequencies of naïve CD4 T cells (Na), precursor T follicular helper cells (pT_FH) and T follicular helper cells (T_FH) that participate in a vaccine response, 2) inhibition of T follicular regulatory cell (T_FR) numbers and/or suppressive capacity, and 3) improving overall T_FH functionality. The ultimate outcome of these interventions would be an increase in functional T_FH cells indicated by higher frequencies of activated T_FH (*T_FH) within circulation and higher levels of vaccine-specific antibody production by B cells. Dendritic cell, DC.