Influence of immune aging on vaccine responses

Abstract

Impaired vaccine responses in older individuals are associated with alterations in both the quantity and quality of the T-cell compartment with age. As reviewed herein, the T-cell response to vaccination requires a fine balance between the generation of inflammatory effector T cells versus follicular helper T (T_FH) cells that mediate high-affinity antibody production in tandem with the induction of long-lived memory cells for effective recall immunity. During aging, we find that this balance is tipped where T cells favor short-lived effector but not memory or T_FH responses. Consistently, vaccine-induced antibodies commonly display a lower protective capacity. Mechanistically, multiple, potentially targetable, changes in T cells have been identified that contribute to these age-related defects, including posttranscription regulation, T-cell receptor signaling, and metabolic function. Although research into the induction of tissue-specific immunity by vaccines and with age is still limited, current mechanistic insights provide a framework for improved design of age-specific vaccination strategies that require further evaluation in a clinical setting.

Keywords: T cells; T-cell receptor; Vaccination; age; antibody; recall response.

Fig 1

Key features of a primary T-cell response after vaccination. In the human T-cell repertoire, approximately 1 in every 10,000 naive cells will be a vaccine (VAX)-specific cell. Upon exposure to vaccination, these cells become activated through engagement of their TCR, and other costimulatory receptors, and undergo massive clonal expansion. During this expansion phase, activated naive cells differentiate into short-lived effector cells or memory precursor cells (MPECs). T_FH cells are generated, likely in a similar manner as MPECs, and provide critical help to B cells for the generation of high-affinity vaccine-specific antibodies. After resolution of vaccine antigen, most effector cells die. A small subset of MPECs survives to become long-lived memory T cells. These memory cells provide protection against subsequent infection or booster vaccination, possibly for decades, via a higher frequency of vaccine-specific cells, their poised effector state, and potential tissue localization. Recall responses after booster vaccination follow the same scheme, however, starting at higher initial frequency of VAX-specific T cells.

Fig 2

Molecular mechanisms of age-associated defects in T-cell responses to vaccines. A mechanistic overview of known age-related changes in key regulators of primary and recall T-cell responses to infections and vaccinations and their functional consequences (orange boxes). Red arrows indicate increases and blue arrows indicate decreases with age.

Fig 3

Potential models for reduced recall responses in aging. Loss of recall responses observed in older individuals could be contributed to 3, not mutually exclusive, scenarios: (Model A) reduced frequency of vaccine-specific memory cells for initial recall, (Model B) less expansion of vaccine-specific memory cells during recall, and (Model C) increased contraction, or poor survival, of vaccine-specific memory postrecall.