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Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children
Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (T(REG)) and of IL-7 homeostatic signalin...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379343/ https://www.ncbi.nlm.nih.gov/pubmed/30809229 http://dx.doi.org/10.3389/fimmu.2019.00213 |
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author | Roider, Julia Ngoepe, Abigail Muenchhoff, Maximilian Adland, Emily Groll, Andreas Ndung'u, Thumbi Kløverpris, Henrik Goulder, Philip Leslie, Alasdair |
author_facet | Roider, Julia Ngoepe, Abigail Muenchhoff, Maximilian Adland, Emily Groll, Andreas Ndung'u, Thumbi Kløverpris, Henrik Goulder, Philip Leslie, Alasdair |
author_sort | Roider, Julia |
collection | PubMed |
description | Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (T(REG)) and of IL-7 homeostatic signaling in maintaining normal-for-age CD4 counts in these individuals. Compared to children with progressive disease, PSP had greater absolute numbers of T(REG), skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory T(REG) (CM T(REG)), indicating active engagement of this subset. Furthermore, PSP secreted higher levels of the immunosuppressive cytokine IL-10 than children who progressed. The frequency of suppressive T(REG), CM T(REG) proliferation, and IL-10 production were all lower in PSP who go on to progress at a later time-point, supporting the importance of an active T(REG) response in preventing disease progression. In addition, we find that IL-7 homeostatic signaling is enhanced in PSP, both through preserved surface IL-7receptor (CD127) expression on central memory T-cells and increased plasma levels of soluble IL-7receptor, which enhances the bioactivity of IL-7. Combined analysis, using a LASSO modeling approach, indicates that both T(REG) activity and homeostatic T-cell signaling make independent contributions to the preservation of CD4 T-cells in HIV-infected children(.) Together, these data demonstrate that maintenance of normal-for-age CD4 counts in PSP is an active process, which requires both suppression of immune activation through functional T(REG), and enhanced T-cell homeostatic signaling. |
format | Online Article Text |
id | pubmed-6379343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63793432019-02-26 Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children Roider, Julia Ngoepe, Abigail Muenchhoff, Maximilian Adland, Emily Groll, Andreas Ndung'u, Thumbi Kløverpris, Henrik Goulder, Philip Leslie, Alasdair Front Immunol Immunology Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (T(REG)) and of IL-7 homeostatic signaling in maintaining normal-for-age CD4 counts in these individuals. Compared to children with progressive disease, PSP had greater absolute numbers of T(REG), skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory T(REG) (CM T(REG)), indicating active engagement of this subset. Furthermore, PSP secreted higher levels of the immunosuppressive cytokine IL-10 than children who progressed. The frequency of suppressive T(REG), CM T(REG) proliferation, and IL-10 production were all lower in PSP who go on to progress at a later time-point, supporting the importance of an active T(REG) response in preventing disease progression. In addition, we find that IL-7 homeostatic signaling is enhanced in PSP, both through preserved surface IL-7receptor (CD127) expression on central memory T-cells and increased plasma levels of soluble IL-7receptor, which enhances the bioactivity of IL-7. Combined analysis, using a LASSO modeling approach, indicates that both T(REG) activity and homeostatic T-cell signaling make independent contributions to the preservation of CD4 T-cells in HIV-infected children(.) Together, these data demonstrate that maintenance of normal-for-age CD4 counts in PSP is an active process, which requires both suppression of immune activation through functional T(REG), and enhanced T-cell homeostatic signaling. Frontiers Media S.A. 2019-02-12 /pmc/articles/PMC6379343/ /pubmed/30809229 http://dx.doi.org/10.3389/fimmu.2019.00213 Text en Copyright © 2019 Roider, Ngoepe, Muenchhoff, Adland, Groll, Ndung'u, Kløverpris, Goulder and Leslie. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Roider, Julia Ngoepe, Abigail Muenchhoff, Maximilian Adland, Emily Groll, Andreas Ndung'u, Thumbi Kløverpris, Henrik Goulder, Philip Leslie, Alasdair Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children |
title | Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children |
title_full | Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children |
title_fullStr | Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children |
title_full_unstemmed | Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children |
title_short | Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children |
title_sort | increased regulatory t-cell activity and enhanced t-cell homeostatic signaling in slow progressing hiv-infected children |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379343/ https://www.ncbi.nlm.nih.gov/pubmed/30809229 http://dx.doi.org/10.3389/fimmu.2019.00213 |
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