Aging Reprograms T Cell Behavior, Weakening Vaccine Responses

The human immune system wanes over time, making older individuals more susceptible to infection and less protected by vaccination.¹ However, while this phenomenon is readily visible and acknowledged, why it occurs or what precisely is happening remains unclear. Researchers from the Allen Institute are aiming to fill this knowledge gap. In a study recently published in Nature, they profiled how immune cells change over the course of a human lifespan, discovering that T cells in older individuals naturally change behaviors in a way that impairs the immune system’s ability to respond to threats.²

During vaccination, the immune system is purposefully exposed to weakened, inactivated, or a component of pathogens so that the body can recognize their molecular structures in the future and mount a more effective response. This process is called immune memory, and memory T and B cells drive the response. Memory T cells can mobilize against pathogens more quickly than naive T cells, while memory B cells mark pathogens for destruction by producing antibodies to specifically target them. However, aging weakens both processes.^3,4

How the immune system reaches this point remains unclear. Claire Gustafson, an immunologist at the Allen Institute, and her colleagues, therefore, sought to better characterize the dynamic effects of aging on immune function. In contrast to past studies which tended to examine singular time points and focused predominantly on individuals over 65 years of age, Gustafson and her team looked at those on the cusp of aging—ages 55 to 65—to better understand how adults transition from functional to diminished immune states. They screened 47 of these individuals, as well as 49 younger adults (25 to 35 years of age), at multiple points across a two-year period to examine how their immune systems responded to annual flu shots.

Gustafson and her team sequenced the RNA from more than 16 million peripheral blood mononuclear cells and categorized them into 71 immune cell subsets. They found that memory T cells in older individuals skewed towards a T helper 2 (T_H2) phenotype. This phenotype is most well known for activating innate immunity components rather than adaptive.⁵ However, here, a T_H2 bias was linked to reduced memory B cell activation and decreased antibody function. “A T_H2-bias shift in memory T cells can change immune responses to viruses and lead to dysregulation of downstream interactions that are required for effective protection such as the production of specific antibodies,” said Gustafson in an email. “Thus, the increasing T_H2-bias in the memory T cell compartment with age may play a critical role in reduced anti-viral immunity broadly in older adults.”

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Age-related immune system decline creates considerable problems for medical practitioners, who grapple with how to best protect individuals with reduced immunity using treatments designed with robust immune responses in mind.⁶ Gustafson hopes that a better understanding of exactly how the immune system changes with age can help in the development of new intervention strategies that increase vaccine effectiveness in older adults. “This may also be an important consideration for not just flu vaccines, but other vaccines that are given repeatedly over the course of a lifespan,” she said.