I Linfociti T Helper Follicolari (TFH)

nell’Immunosenescenza

Gilda Varricchi, MD, PhD

Department of Translational Medical Sciences (DiSMeT)

Center for Basic and Clinical Immunology Research (CISI)

University of Naples Federico II

Immunology of Aging Represents a Paradox of

Low-Grade Inflammation (Inflammaging),

Immunodeficiency, Autoimmunity,

and Cancer

Is There a Common Denominator?

Cells of the innate (macrophages, mast cells, neutrophils, etc.) and adaptive

arms (CD4+ and CD8+ lymphocytes, TFH cells, etc.) exhibit altered phenotypes

in aging

Immunefrailty is characterised by increased susceptibility to infections, cancer,

cardiovascular and autoimmune disorders: top killers of elderly people

T Follicular Helper (TFH) cells

play a fundamental role in these disorders

IMMUNEFRAILTY and T Follicular Helper (TFH) Cells in Aging

Origins, Functions, and Regulation of TFH Cells

• T follicular helper (TFH) cells were first identified in 2000 in human tonsils as a

subset of CD4+ cells expressing the chemokine receptor CXCR5 and providing

help to B cells [JEM, 192: 1545, 2000; JEM, 192: 1553, 2000]

• Subsequently, TFH cells were identified in human peripheral blood

• TFH cells are specialized in providing “cognate help” to B cells and are

fundamentally required for the production of immunoglobulin (IgM, IgG, IgE) by

plasma cells

AGING

TUMORS

ATHEROSCLEROSIS

MYOCARDIAL

INFARCTION

AUTOIMMUNE

DISORDERS

BACTERIAL

AND VIRAL

INFECTIONS

HELMITH

INFECTIONS

ALLERGIC

DISORDERS

IMMUNODEFICIENCIES

VASCULITIS

Tfh

CELLS

Varricchi et al., Proceedings of the 30° Collegium Internationale Allergologicum 2014

Immunoglobulins

Plasma Cells

Varricchi et al., Allergy, 71:1086, 2016

T Follicular Helper (TFH) Cell Subsets

Gowthaman et al., Science. 30: eaaw6433, 2019

T Follicular Regulatory TFR Cells

• In 2011, several groups described that T regulatory (TREG) cells can undergo

functional specialization to suppress B cells and antibody production [Nat.

Med., 17: 975, 2011; Nat. Med. 17: 983, 2011; J.I. 187: 4553, 2011]

• This specialized population of T cells was named T follicular regulatory (TFR)

cells

• TFR cells are present in secondary lymphoid organs and in peripheral blood

• TFR cells express CXCR5, BCL6, ICOS, and PD-1, like TFH, but also express

FOXP3

Stebegg et al., Front. Immunol. 9: 9:2469, 2018

Modulation of Tfh –B cell Interaction by Tfr cells

• cTFH (CXCR5+ PD-1+) from elderly are reduced in the frequency, compared to young

donors [JI 193: 3528, 2014]

• cTFH from elderly have decreased B cell help ability

• Elderly have reduced increase in titers of the vaccine-induced IgM and IgG compared

to young donors

• cTFH from elderly have increased expression of ICOS

Circulating TFH Cells (cTFH) in the Elderly

Herati et al., J. Immunol. 193: 3528, 2014

Tfh from elderly are decreased

and express more ICOS

Defective TFH Cells Functions and Increased TFR Cells in Aging

• In aged mice there is an increase in cTFR cells

• The ratio TFH/ TFR cells is an important factor in humoral immunity [JCI 124: 5191,

2014] and is altered in aging

• TFH cells from aged mice and humans have defects in antigen-specific B cell stimulation

[Plos Biology 2019; Curr. Opin. Immunol. 59: 9, 2019]

• In aging, there is an overall decrease in B cell responses [Cell. Rep. 12:163, 2015] which

accounts for reduced vaccine response and infection resolution

Gustafson et al., Clin. Sci. 132: 1925, 2018Nikolich-Zugich, Nat. Immunol. 2018

• TFH are involved in a variety of pathological conditions associated with aging (autoimmune disorders,

cancer, atherosclerosis, myocardial infarction, etc.)

• In elderly, there is a reduction of TFH and increase in TFR cells

• Alterations of TFH/TFR ratio in the elderly result in lower production of antigen-specific antibodies

• Better knowledge of subpopulations of TFH cells in the elderly appears necessary to understand the

development and evolution of autoimmunr disorders, atherosclerosis, myocardial infarction and

cancer

Conclusions

Acknowledgments

Amato de Paulis, M.D.

Giuseppe Spadaro M.D.

Arturo Genovese, M.D

Francesca Wanda Rossi M.D, Ph.D.

Antonio Pecoraro M.D.

Remo Poto M.D.

Maria Rosaria Galdiero MD, PhD

Stefania Loffredo, Ph.D.

Gjada Criscuolo, M. Sc.

Gianni Marone M.D.

Stephen R. Durham, M.D.

Mohamed Shamji, M.D.

Guy W. Scadding, M.D.

Esther Steveling, M.D.

Mongkol Lao-Araya, M.D.Natalia C. Francisco, Ph.D

• The percentage of Tfh cells is increased in ApoE mice which have a

propensity to develop atherosclerosis, compared to control mice.

• ApoE mice have increased production of IgG auto-antibodies.

• The myosin heavy chain (MYHCA), released by necrotic

cardiomyocytes, is the main auto-antigen which activates Tfh cells

following experimental myocardial infarction.Rieckmann et al. J. Clin. Invest. 2019

Ryu H et al., Nat. Immunol. 2018

J Clin Invest. 2013 Jul;123(7):2873-92.

J Clin Invest. 2019 Aug 13;130:4922-4936.

Front Immunol. 2018 Jul 17;9:1637.

Allergy. 2016 Aug;71(8):1086-94.

Nat Immunol. 2018 Jun;19(6):583-593.

Cinetica della Risposta Immunitaria ad un’Infezione Tipica

Attivazione

dell’immunità

innata

Formazione

degli anticorpi

Il decorso temporale di una tipica risposta anticorpale

La risposta immunitaria acquisita determina lo sviluppo di una rispostaanticorpale più rapida e più efficace alla seconda esposizione ad un antigene

Tempo 0