High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults

Julia Roider; Takashi Maehara; Abigail Ngoepe; Duran Ramsuran; Maximilian Muenchhoff; Emily Adland; Toby Aicher; Samuel W. Kazer; Pieter Jooste; Farina Karim; Warren Kuhn; Alex K. Shalek; Thumbi Ndung'u; Lynn Morris; Penny L. Moore; Shiv Pillai; Henrik Kløverpris; Philip Goulder; Alasdair Leslie

doi:10.3389/fimmu.2018.01975

High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults

Julia Roider, Takashi Maehara, Abigail Ngoepe, Duran Ramsuran, Maximilian Muenchhoff, Emily Adland, Toby Aicher, Samuel W. Kazer, Pieter Jooste, Farina Karim, Warren Kuhn, Alex K. Shalek, Thumbi Ndung'u, Lynn Morris, Penny L. Moore, Shiv Pillai, Henrik Kløverpris, Philip Goulder^*, Alasdair Leslie

^*Corresponding author af dette arbejde

13 Citationer (Scopus)

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Abstract

Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (T_FH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, T_FH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific T_FH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific T_FH in pediatric lymphoid tissue is accompanied by increased T_FH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific T_FH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.

Originalsprog	Engelsk
Artikelnummer	1975
Tidsskrift	Frontiers in Immunology
Vol/bind	9
Antal sider	14
ISSN	1664-3224
DOI	https://doi.org/10.3389/fimmu.2018.01975
Status	Udgivet - 2018

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10.3389/fimmu.2018.01975Licens: CC BY

High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not AdultsForlagets udgivne version, 2,76 MBLicens: CC BY

Citationsformater

Roider, J., Maehara, T., Ngoepe, A., Ramsuran, D., Muenchhoff, M., Adland, E., Aicher, T., Kazer, S. W., Jooste, P., Karim, F., Kuhn, W., Shalek, A. K., Ndung'u, T., Morris, L., Moore, P. L., Pillai, S., Kløverpris, H., Goulder, P., & Leslie, A. (2018). High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults. Frontiers in Immunology, 9, [1975]. https://doi.org/10.3389/fimmu.2018.01975

Roider, J, Maehara, T, Ngoepe, A, Ramsuran, D, Muenchhoff, M, Adland, E, Aicher, T, Kazer, SW, Jooste, P, Karim, F, Kuhn, W, Shalek, AK, Ndung'u, T, Morris, L, Moore, PL, Pillai, S, Kløverpris, H, Goulder, P & Leslie, A 2018, 'High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults', Frontiers in Immunology, bind 9, 1975. https://doi.org/10.3389/fimmu.2018.01975

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title = "High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults",

abstract = "Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment na{\"i}ve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.",

keywords = "Broadly neutralizing antibodies (bnAb), Follicular CD8 T-cells, Germinal center, Pediatric HIV infection, T-follicular helper cells (Tfh), T-follicular regulatory helper cells (Tfreg), Vaccination",

author = "Julia Roider and Takashi Maehara and Abigail Ngoepe and Duran Ramsuran and Maximilian Muenchhoff and Emily Adland and Toby Aicher and Kazer, {Samuel W.} and Pieter Jooste and Farina Karim and Warren Kuhn and Shalek, {Alex K.} and Thumbi Ndung'u and Lynn Morris and Moore, {Penny L.} and Shiv Pillai and Henrik Kl{\o}verpris and Philip Goulder and Alasdair Leslie",

year = "2018",

doi = "10.3389/fimmu.2018.01975",

language = "English",

volume = "9",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults

AU - Roider, Julia

AU - Maehara, Takashi

AU - Ngoepe, Abigail

AU - Ramsuran, Duran

AU - Muenchhoff, Maximilian

AU - Adland, Emily

AU - Aicher, Toby

AU - Kazer, Samuel W.

AU - Jooste, Pieter

AU - Karim, Farina

AU - Kuhn, Warren

AU - Shalek, Alex K.

AU - Ndung'u, Thumbi

AU - Morris, Lynn

AU - Moore, Penny L.

AU - Pillai, Shiv

AU - Kløverpris, Henrik

AU - Goulder, Philip

AU - Leslie, Alasdair

PY - 2018

Y1 - 2018

N2 - Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.

AB - Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.

KW - Broadly neutralizing antibodies (bnAb)

KW - Follicular CD8 T-cells

KW - Germinal center

KW - Pediatric HIV infection

KW - T-follicular helper cells (Tfh)

KW - T-follicular regulatory helper cells (Tfreg)

KW - Vaccination

U2 - 10.3389/fimmu.2018.01975

DO - 10.3389/fimmu.2018.01975

M3 - Journal article

C2 - 30258437

AN - SCOPUS:85053116226

SN - 1664-3224

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1975

ER -

High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults

Abstract

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