The emerging role of T follicular helper (TFH) cells in aging: Influence on the immune frailty

https://doi.org/10.1016/j.arr.2020.101071Get rights and content

Highlights

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    Immunosenescence is characterized by poor response to vaccine and higher incidence of infections, cancer, cardiovascular and autoimmune diseases.

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    Immunosenescence has been associated with chronic low-grade inflammation but its underlying mechanisms are still not fully understood.

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    T follicular helper (TFH) cells provide help to B cell for antibody production. Phenotypic and functional changes in TFH cells occur in aging.

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    T follicular regulatory (TFR) cells have opposing roles to TFH cells in regulating immunity. The ratio TFH/TFR cells is important in aging.

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    Recent findings suggest that TFH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.

Abstract

The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (TFH) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of TFH cells have been identified in humans and mice and modifications in TFH cell phenotype and function progressively occur with age. Dysfunctional TFH cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (TFR) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to TFH cells in regulating immunity. Indeed, changes in TFH/TFR cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both TFH cells and TFR cells that occur in aging and recent findings suggesting that TFH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.

Introduction

Physiological aging is characterized by a number of interrelated processes that ultimately leads to the emergence of characteristic phenotypes, including increased susceptibility to several chronic inflammatory diseases, disability and death (Organization, 2015; United Nations, 2019). Central to this paradigm are changes in the immune system, characterized by the chronic low‐grade proinflammatory state that affect many older individuals, even when they are apparently healthy and free of diseases and risk factors (Franceschi et al., 2007; Bektas et al., 2017; Hernandez-Segura et al., 2018). Initial studies found that blood concentrations of proinflammatory cytokines (e.g., IL-6) (Ferrucci et al., 1999, 2005) and chemokines (CCL2, CXCL10) (Antonelli et al., 2006) increase with age. Adjusting for cardiovascular risk factors and morbidity the effect of age on IL-6 was reduced (Ferrucci et al., 2005). Several recent studies have found no relationship between high IL-6 levels and frailty when the healthy status of older subjects was strictly controlled (Reiner et al., 2009; Baylis et al., 2013; Gale et al., 2013). A recent study found that the plasma levels of IL-6 were increased in both male and females nonagenarians compared to young controls (Nevalainen et al., 2019). It is possible that the associations between circulating cytokines/chemokines and aging are due at least in part to increases in chronic ailments associate with age rather than to biological aging itself.

Despite the complexity and some inconsistencies regarding the association between circulating inflammatory mediators and frailty, dysregulated immune functions are considered pivotal of most biologic changes occurring in physiological aging and in age‐related diseases (Bektas et al., 2017; Franceschi et al., 2017b; 2018; Furman et al., 2019). However, the intrinsic complexity of the innate and adaptive immune system mandates caution in studying the aging processes (Nikolich-Zugich, 2018). An additional level of complexity derives from the recent identification of several subsets of T (Thommen et al., 2018; Li et al., 2019; Wen et al., 2019) and B lymphocytes (Tsou et al., 2016), dendritic cells (DCs) (Binnewies et al., 2019), macrophages (Chevrier et al., 2017; Aran et al., 2019; Borriello et al., 2019), mast cells (Gentek et al., 2018; Varricchi and de Paulis, 2019; Varricchi and Marone, 2020), neutrophils (Fridlender et al., 2009; Sagiv et al., 2015; Galdiero et al., 2018) and other immune lineages.

Section snippets

Frailty and immune frailty

Frailty is a clinical syndrome closely associated with aging and characterized by the loss of homeostatic reserve in multiple physiological systems (Clegg et al., 2013; Society, 2014). Frailty is recognized as a syndrome disparate from disability and co-morbidity (Fried et al., 2004) which conveys an increased risk of morbidity, disability and mortality (https://www.ncbi.nlm.nih.gov/pubmed/28689563). The canonical definition of “frailty” includes a series of heterogeneous conditions, ranging

T follicular helper (TFH) cells

In the 1980s, it was demonstrated that two CD4+ T cell subsets, T helper 1 (TH1) and TH2 cells, may induce distinct patterns of antibody isotype switching (Mosmann et al., 1986; Stevens et al., 1988). In 2000, this dogma was challenged by the discovery that certain CD4+ T helper cells, expressing CXC-chemokine receptor 5 (CXCR5), the receptor that facilitates homing to the B cell follicle (Ansel et al., 1999), possess superior helper abilities (Breitfeld et al., 2000; Schaerli et al., 2000; Kim

Phenotypes of T follicular regulatory (TFR) cell subsets

In 2011, three independent groups reported that T regulatory (Treg) cells can undergo functional specialization to suppress antibody responses (Chung et al., 2011; Linterman et al., 2011; Wollenberg et al., 2011). This specialized population of Treg cells was named T follicular regulatory (TFR) cells. These cells are present in secondary lymphoid organs and in peripheral blood (Sage et al., 2014a; Wing et al., 2017; Clement et al., 2019). TFR cells in mice express CXCR5, ICOS, PD-1, and Bcl6 (

T‐cell changes with age

With advancing age the size of the naïve T‐cell pool decreases in both humans and mice (De Paoli et al., 1988; Utsuyama et al., 1992; Lazuardi et al., 2005). In adult humans, the pool of naïve T cells is maintained by peripheral cell division, rather than thymic output (den Braber et al., 2012). The decreasing pool of naïve T cells with age is attributed to antigen‐dependent activation of T cells throughout life (Su et al., 2013) and correlates with a reduced antibody response to vaccination (

TFH cells in aging

Naïve T cell responses are pivotal in defense against new pathogens and may be affected by age. Immune protection from vaccination in older subjects relies mainly on recall responses by expanding memory T cells. Dysfunctions in both naïve and memory CD4+ T cell compartments contribute to altered TFH responses in aging (Gustafson et al., 2018). After T‐cell priming, TFH differentiation requires the integration of a number of signals that culminate in

Bcl6 expression and TFH cell migration into

TFR cells in aging

TFH/TFR cell ratio is an important factor in humoral immunity in both humans and mice (Sage et al., 2014a). Sage and collaborators reported that aged mice develop higher percentage of TFH and TFR cells, with proportionally more TFR cells, compared to young mice following antigen initiation (Sage et al., 2015b). This skews the TFH/TFR ratio towards suppressive TFR cells. Furthermore, in antigen-specific in vitro and in vivo assays, the stimulatory capacity of aged TFH cells was diminished

Concluding remarks and perspectives

Frailty is a syndrome for an increasingly elderly population whose pathogenesis remains largely unknown (Clegg et al., 2013; Society, 2014). Low-grade inflammation has a key pathophysiological role in frailty (Franceschi et al., 2007; Li et al., 2011; Yao et al., 2011; Franceschi et al., 2017a) and several cells of innate and adaptive immune system exhibit altered phenotypes and functions in aging. In mice, several changes in TFH phenotypes and functions occur in aging (Perkey et al., 2012; Yu

Author contributions

Conceptualization: GV, LB, MHS, GR; Original draft preparation: GV, LB, GR; Final editing: GV, LB, RP, AP, MHS, GR. All authors contributed to reviewing the current literature and writing of the manuscript and approved the final version of the paper.

Funding

This work was supported in part by grants from CISI-Lab Project (University of Naples Federico II), CRèME Project and TIMING Project (Regione Campania).

Declaration of conflicting interest

None.

Acknowledgments

The authors apologize to the many researchers who have contributed importantly to this field and whose work has not been cited due to space and citation restrictions. The authors thank Prof. Gianni Marone for intellectual input, Dr. Gjada Criscuolo for critical reading of the manuscript and medical graphic artist Fabrizio Fiorbianco for preparing the figures. Dr. Leonardo Bencivenga has been supported by a research grant provided by the Cardiopath PhD program.

References (214)

  • I. den Braber et al.

    Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans

    Immunity

    (2012)
  • W. Drew et al.

    Inflammation and neutrophil immunosenescence in health and disease: targeted treatments to improve clinical outcomes in the elderly

    Exp. Gerontol.

    (2018)
  • L. Ferrucci et al.

    The origins of age-related proinflammatory state

    Blood

    (2005)
  • C. Franceschi et al.

    Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans

    Mech. Ageing Dev.

    (2007)
  • C. Franceschi et al.

    Inflammaging and’ Garb-aging’

    Trends Endocrinol. Metab.

    (2017)
  • Z.G. Fridlender et al.

    Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN

    Cancer Cell

    (2009)
  • S. He et al.

    Senescence in health and disease

    Cell

    (2017)
  • J. He et al.

    Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure

    Immunity

    (2013)
  • A. Hernandez-Segura et al.

    Hallmarks of cellular senescence

    Trends Cell Biol.

    (2018)
  • M. Jergovic et al.

    Intrinsic and extrinsic contributors to defective CD8+ T cell responses with aging

    Exp. Gerontol.

    (2018)
  • S.L. LaPorte et al.

    Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system

    Cell

    (2008)
  • A. Agrawal et al.

    Increased IL-21 secretion by aged CD4+T cells is associated with prolonged STAT-4 activation and CMV seropositivity

    Aging (Albany NY)

    (2012)
  • A. Agrawal et al.

    Role of Dendritic Cells in Inflammation and Loss of Tolerance in the Elderly

    Front. Immunol.

    (2017)
  • A. Aiello et al.

    Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention

    Front. Immunol.

    (2019)
  • J. Albrengues et al.

    Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice

    Science

    (2018)
  • K.M. Ansel et al.

    In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines

    J. Exp. Med.

    (1999)
  • D. Aran et al.

    Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

    Nat. Immunol.

    (2019)
  • A.T. Bauquet et al.

    The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells

    Nat. Immunol.

    (2009)
  • D. Baylis et al.

    Immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people

    Age Dordr. (Dordr)

    (2013)
  • E. Becht et al.

    Immune and stromal classification of colorectal Cancer Is associated with molecular subtypes and relevant for precision immunotherapy

    Clin. Cancer Res.

    (2016)
  • A. Bektas et al.

    Human T cell immunosenescence and inflammation in aging

    J. Leukoc. Biol.

    (2017)
  • S.E. Bentebibel et al.

    Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination

    Sci. Transl. Med.

    (2013)
  • M. Binnewies et al.

    Unleashing Type-2 dendritic cells to drive protective antitumor CD4(+) t cell immunity

    Cell

    (2019)
  • F. Borriello et al.

    Innate immune modulation by GM-CSF and IL-3 in health and disease

    Int. J. Mol. Sci.

    (2019)
  • R. Bos et al.

    CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes

    Cancer Res.

    (2010)
  • R. Bos et al.

    Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment

    Oncoimmunology

    (2012)
  • D. Botta et al.

    Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection

    Nat. Immunol.

    (2017)
  • D. Breitfeld et al.

    Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production

    J. Exp. Med.

    (2000)
  • S.K. Butcher et al.

    Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans

    J. Leukoc. Biol.

    (2001)
  • R. Cabrita et al.

    Tertiary lymphoid structures improve immunotherapy and survival in melanoma

    Nature

    (2020)
  • S. Chevrier et al.

    An immune atlas of clear cell renal cell carcinoma

    Cell

    (2017)
  • J.Y. Choi et al.

    Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity

    .

    (2015)
  • Y.S. Choi et al.

    LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6

    Nat. Immunol.

    (2015)
  • Y. Chung et al.

    Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions

    Nat. Med.

    (2011)
  • M. Clement et al.

    Control of the T follicular helper-germinal center B-cell axis by CD8(+) regulatory T cells limits atherosclerosis and tertiary lymphoid organ development

    Circulation

    (2015)
  • R.L. Clement et al.

    Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses

    Nat. Immunol.

    (2019)
  • E. Cretney et al.

    The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells

    Nat. Immunol.

    (2011)
  • L. Cristinziano et al.

    Anaplastic thyroid Cancer cells induce the release of mitochondrial extracellular DNA traps by viable neutrophils

    J. Immunol.

    (2020)
  • U. De Fanis et al.

    T-lymphocytes expressing CC chemokine receptor-5 are increased in frail older adults

    J. Am. Geriatr. Soc.

    (2008)
  • J. Deng et al.

    T follicular helper cells and T follicular regulatory cells in rheumatic diseases

    Nat. Rev. Rheumatol.

    (2019)

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