Why vaccine response with age is impaired

Why vaccine response with age is impaired

Aging is associated with a decline in immune function, contributing to the increased susceptibility to infectious diseases and higher incidence of malignant disease. As a consequence of the impaired adaptive immune response, vaccinations are less efficacious. While naive T cell responses are particularly compromised, memory T cell responses are also impaired as documented by the reduced efficacy of annual influenza vaccinations or the poor recall response to varicella zoster immunization.

Most studies exploring mechanistic defects have focused on the early stages of an immune response. In contrast to the mouse, age-associated changes in T cell repertoire composition are not sufficient to explain the failure in human immune competence with age.

The number of naive T cells declines with age; however, at least for CD4+ T cells, the decline is modest , and the T cell receptor (TCR) repertoire continues to be sufficiently diverse in older adults to include T cell specificities to most if not all exogenous antigens. An increased threshold to respond to TCR triggering due to increased expression of the dual-specific phosphatase 6 is likely to compromise stimulation by low-affinity peptides for naive cells.

Later phases of the T cell response have been less explored for age-associated defects. Subsequent to TCR stimulation, antigen-specific T cells exponentially expand and differentiate into effector cells. Most of these expanded cells undergo apoptosis; a few of them survive as long-lived memory cells. CD8+ T cells only require a short encounter with antigen to clonally expand and develop into effector cells. The cell surface marker KLRG1 and the interleukin-7 (IL-7) receptor are useful to identify murine CD8+ effector T cells that survive and transition into memory cells.

CD4+ T cells require ongoing antigenic stimulation during clonal expansion. Transition into memory cells is dependent on the strength of the TCR signal, and only high-affinity T cells survive. The mechanisms regulating CD4+ effector cell clonal downsizing versus memory cell differentiation are undetermined. Ly6C has been suggested as phenotypic marker of CD4+ memory cell precursors in the murine effector cell population but does not exist in humans.

To identify age-associated defects in memory cell formation, authors profiled activated CD4+ T cells and found an increased induction of the ATPase CD39 with age. CD39+ CD4+ T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis.

Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate.

Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.