Review
Regulatory T cells and vaccine effectiveness in older adults. Challenges and prospects

https://doi.org/10.1016/j.intimp.2021.107761Get rights and content

Highlights

  • Vaccines are less effective in older adults.

  • Aging is associated with increased regulatory T-cells (Tregs) function.

  • Tregs can hamper vaccine effectiveness in advanced ages.

  • Tregs modulation could improve vaccine efficacy in older ages.

Abstract

Since the discovery of lymphocytes with immunosuppressive activity, increasing interest has arisen in their possible influence on the immune response induced by vaccines. Regulatory T cells (Tregs) are essential for maintaining peripheral tolerance, preventing autoimmune diseases, and limiting chronic inflammatory diseases. However, they also limit beneficial immune responses by suppressing anti-infectious and anti-tumor immunity. Mounting evidence suggests that Tregs are involved, at least in part, in the low effectiveness of immunization against various diseases where it has been difficult to obtain protective vaccines. Interestingly, increased activity of Tregs is associated with aging, suggesting a key role for these cells in the lower vaccine effectiveness observed in older people. In this review, we analyze the impact of Tregs on vaccination, with a focus on older adults. Finally, we address an overview of current strategies for Tregs modulation with potential application to improve the effectiveness of future vaccines targeting older populations.

Introduction

The prevalence and severity of viral and bacterial infections including influenza, pneumococcal disease, respiratory syncytial virus (RSV), herpes zoster, and more recently severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are notably increased among older adults compared to younger individuals [1], [2]. Although vaccination against several infections is the most cost-effective strategy for preventing infectious diseases [3], its effectiveness is often reduced in older people compared with younger individuals [1], [4]. Consequently, and given the rapidly aging population in both developed and developing countries, the search for new strategies to improve vaccine effectiveness in that age group is high priority [5].

Our understanding of the mechanisms underlying immunosenescence is still limited and much remains to be learned to improve the effectiveness of next-generation vaccines. So far, we know that the aging process is associated with continuous exposure to new and persistent antigens and the need to replace old cells, leading to profound remodeling of the immune system [6], [7]. These changes could negatively impact vaccine effectiveness in older people [7]. One of the changes associated with immunosenescence is an intriguing increase in the frequency of regulatory T cells (Tregs) in peripheral blood and lymphoid tissues [8], [9], [10], [11], [12]. Tregs are CD4+ CD25+ lymphocytes characterized by a high expression of forkhead/winged-helix family transcription factor (Foxp3) and, in humans, by low levels of the alpha chain of interleukin-7 (IL-7) receptor (CD127). These cells exert an important immunosuppressive activity to prevent deleterious effects caused by hyperstimulation of the immune system [13].

Different strategies have been developed to improve vaccine effectiveness in older people. These strategies have focused mainly on the use of 1) higher doses of antigens, 2) new adjuvants, 3) alternative administration routes, 4) senolytics (drugs that selectively induce apoptosis in senescent cells without harming healthy cells) and, 5) immunomodulatory drugs [14], [15], [16]. In recent years, there has been increasing research regarding the use of Tregs modulation to improve the immunogenicity and effectiveness of vaccines. Due to the immunosuppressive effect of Tregs, these strategies are based on their temporary depletion or inhibition using molecular adjuvants during the induction phase of the immune response [17], [18].

The objective of this minireview is to update the current knowledge of Tregs role in vaccine-induced immune responses with a focus on older adults. Besides, we address current approaches to improve vaccine effectiveness by modulating Tregs activity with potential application in future vaccines targeting older populations.

Section snippets

Tregs overview

The existence of suppressive lymphocytes was proposed in the early 1970s [19], but the first phenotypic marker identified for these cells, interleukin-2 receptor alpha chain or CD25, was discovered 25 years later in mice [20]. After that, several groups simultaneously reported the presence of a CD4+ CD25+ T cell population with immunosuppressive activity in humans [21], [22], [23], [24], [25]. Shortly after, Foxp3 was identified as a key molecule involved in the development and

Tregs in older adults

Age-related changes in the immune system were firstly described in mice in the late 70 s and were mainly focused on age-dependent changes in macrophages and lymphocytes [35], [36]. Due to their relatively long lifespan, lymphocytes exhibit functional transformations throughout life [7]. These changes include a reduction in the CD4+/CD8+ ratio, impaired development of CD4+ T follicular helper cells with a low number of B cells, reduced cytotoxic activity of Natural Killer T-cells (NKTs), poor

Human versus mouse Tregs

Most of the current information on Tregs biology during aging is derived from experimental studies in mice, although increasing data are being obtained from humans [49], [50], [51], [52], [53]. However, there are some considerations to keep in mind when extrapolating data from mice to humans. Studies of Tregs in mice are often performed from samples of lymph nodes and spleen, whereas most human studies involve analyses of Tregs in blood. Besides, laboratory mice are housed in pathogen-free

Deleterious effects of Tregs on vaccine-induced immune responses

Growing evidence shows that Tregs expansion and activation during the immunization process, can be involved, in the reduced effectiveness of certain vaccines. The inhibitory effects of Tregs on vaccine-induced immune responses have been experimentally demonstrated in different murine models of Tregs depletion. The DEREG (DEpletion of REGulatory T cells) mouse, is a transgenic model in which Foxp3 + Tregs can be specifically depleted to study the specific function of these cells during

Tregs and effectiveness of vaccines for older adults

At least four anti-infectious vaccines are currently recommended for older adults, including vaccines against influenza, pneumococcal disease, herpes zoster, and a booster against tetanus and diphtheria. These strategies of vaccination help to mitigate the severity of these diseases, but often fail to induce protective immunity in older adults [79]. Growing evidence suggests that Tregs are involved in the reduced effectiveness of these vaccines, as discussed below.

What can we expect on SARS-CoV-2 vaccination?

SARS-CoV-2 infection (COVID-19) severity has been associated with a high level of inflammation and a cytokine storm syndrome, more frequently observed in older people. These manifestations are associated with dysregulated funtions of the innate and adaptive immune response [107], [108], [109]. Even though different patterns and immunophenotypes have been reported for different clinical forms of COVID-19, the role of Tregs in the immunopathogenesis of COVID-19 is so far not fully understood [110]

Novel approaches of Tregs modulation to improve vaccine effectiveness

Overall, vaccines that are recommended in older adults fail to elicit long-lasting immune responses. Although research on vaccine-induced immune responses in older adults are still limited, current knowledge provides a framework for improved vaccination strategies designed toward older people [122]. Several approaches are currently in place to improve vaccine effectiveness in this population mainly focused on the use of adjuvants, higher antigen doses, and alternative routes of immunization

Challenges on Tregs modulation for vaccine improvement

Given the great importance of Tregs in the control of the immune response, it is easy to understand that any attempt to modify their activity can influence the immunoregulatory activity. In this sense, immunotoxic reactions are the main adverse effects associated with adjuvanted vaccines and the main concern for the clinical use of new adjuvant formulations [175]. Specifically, the reduction of the Tregs activity can potentially lead to the development of inflammatory or autoimmune responses

Conclusions and perspectives

Unraveling the mechanisms involved in reduced vaccine immune responses and their low effectiveness, particularly in the context of aging, is an area of intense research interest. Different strategies used to improve vaccine outcomes in older individuals include the use of adjuvants, higher vaccine doses or booster vaccination, but such attempts have been of limited benefit. Evidence suggests that Tregs accumulation associated with immunosenescence is in part responsible for the poor response

Author contributions

All authors contributed to the writing of this manuscript. The funding agencies did not have any role in decision to publish, or preparation of the manuscript. The authors read and approved the final article.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

Pró-Reitoria de Pesquisa SisPROPe n° 3260. São Paulo State University (UNESP) (to ABD).

Fundacão de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant No. 2018/15187-2). (to ABD).

Miguel Servet CP19/00008 contract from Instituto de Salud Carlos III co-funded by ERDF/ESF, “A way to make Europe”/”Investing in your future” (to AP).

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