ReviewRegulatory T cells and vaccine effectiveness in older adults. Challenges and prospects
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).
References (179)
- et al.
Vaccination in the elderly: an immunological perspective
Trends Immunol.
(2009) - et al.
Immunosenescence: Implications for response to infection and vaccination in older people
Maturitas.
(2015) - et al.
Blockage of regulatory T cells augments induction of protective immune responses by influenza virus-like particles in aged mice
Microbes Infect.
(2017) - et al.
A systems-level overview of immune cell biology and strategies for improving vaccine responses
Exp. Gerontol.
(2019) - et al.
Molecular adjuvants that modulate regulatory T cell function in vaccination: A critical appraisal
Pharmacol. Res.
(2018) - et al.
Negligible effect of sodium chloride on the development and function of TGF-β-induced CD4+ Foxp3+ regulatory T cells
Cell Rep.
(2019) - et al.
CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence
Clin Immunol.
(2004) - et al.
Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor
Immunity
(2009) - et al.
Regulatory T-cell response and tumor vaccine-induced cytotoxic T lymphocytes in human melanoma
Hum. Immunol.
(2004) - et al.
Blockage of regulatory T cells augments induction of protective immune responses by influenza virus-like particles in aged mice
Microbes Infect.
(2017)
Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection
Mucosal Immunol.
Aging disturbs the balance between effector and regulatory CD4+ T cells
Exp. Gerontol.
Circulating pneumococcal specific plasma and memory B cells in the elderly two years after pneumococcal conjugate versus polysaccharide vaccination
Vaccine
Adult Pneumonia Study Group-Japan (APSG-J). Serotype-specific effectiveness of 23-valent pneumococcal polysaccharide vaccine against pneumococcal pneumonia in adults aged 65 years or older: a multicentre, prospective, test-negative design study
Lancet Infect. Dis.
Immunosenescence and human vaccine immune responses
Immun Ageing.
Immunosenescence and inflammaging: risk factors of severe COVID-19 in older people
Front. Immunol.
A guide to vaccinology: from basic principles to new developments
Nat. Rev. Immunol.
Precision Medicine and Vaccination of older adults: from reactive to proactive (a mini-review)
Gerontology.
Regulatory T cells and the immune aging process: a mini-review
Gerontology.
CD4+CD25+Foxp3+ T cells and CD4+CD25− Foxp3+ T cells in aged mice
J. Immunol.
Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice
J. Leukoc. Biol.
Aging is associated with increased regulatory T-cell function
Aging Cell
Age-related changes in CD4+CD25+FOXP3+ regulatory T cells and their relationship with lung cancer
PLoS ONE
FOXP3+ regulatory T cells and their functional regulation
Cell. Mol. Immunol.
Adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine
Hum Vaccin.J
Vaccines for the elderly: current use and future challenges
Immun Ageing.
Targeting regulatory T cells to improve vaccine immunogenicity in early life
Front. Microbiol.
Cell interactions in the induction of tolerance: the role of thymic lymphocytes
Immunology
Immunologic tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25): breakdown of a single mechanism of selftolerance causes various autoimmune diseases
J. Immunol.
CD4+CD25high regulatory cells in human peripheral blood
J. Immunol.
Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood
J. Exp. Med.
Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood
J. Exp. Med.
Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro
Eur. J. Immunol.
Human anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population
Eur. J. Immunol.
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Nat. Immunol.
An essential role for Scurfin in CD4+CD25+ T regulatory cells
Nat. Immunol.
Cutting edge: foxp3+ CD4+ CD25+ regulatory T cells induced by IL-2 and TGF-β are resistant to Th17 conversion by IL-6
J. Immunol.
Transcriptional regulation of differentiation and functions of effector T regulatory cells
Cells
New insights into regulatory T cells: exosome- and non-coding RNA-mediated regulation of homeostasis and resident Treg cells
Front. Immunol.
Stability and maintenance of Foxp3+ Treg cells in non-lymphoid microenvironments
Front. Immunol.
Emerging functions of regulatory T cells in tissue homeostasis
Front. Immunol.
Suppressor cells in immunosenescence
Fed Proc
Cellular immunosenescence
Gerontology.
Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly
J. Immunol.
S, M, Eaton, P, A, Lanthier, M, Tighe, L, Haynes, The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice
Aging Cell
Understanding immunosenescence to improve responses to vaccines
Nat. Immunol.
Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors
Nat. Immunol.
Cited by (6)
Immune system aging and the aging-related diseases in the COVID-19 era
2022, Immunology LettersCitation Excerpt :While tTregs numbers are (for intuitively obvious reasons) reduced with advancing age, these of peripheral Tregs induced during the adaptive response to an antigenic challenge (iTregs) not only do not dwindle, but in fact increase in the elderly. We were among the first to show this phenomenon at the beginning of the 21st century, and were followed by many similar observations [46–52]. This finding may in part explain the decreased effectiveness of the immune responses in the aged (relatively more “braking”).
Nanomaterial for Adjuvants Vaccine: Practical Applications and Prospects
2024, Indonesian Journal of ChemistryPsychotropic drugs interaction with the lipid nanoparticle of COVID-19 mRNA therapeutics
2022, Frontiers in PharmacologyClinical perspectives on the age-related increase of immunosuppressive activity
2022, Journal of Molecular Medicine