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Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage

Sonwabile Dzanibe, Katie Lennard, Agano Kiravu, Melanie S. S. Seabrook, Berenice Alinde, Susan P. Holmes, Catherine A. Blish, Heather B. Jaspan and Clive M. Gray
J Immunol January 1, 2022, 208 (1) 27-37; DOI: https://doi.org/10.4049/jimmunol.2100503
Sonwabile Dzanibe
*Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
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Katie Lennard
†Division of Computational Biology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
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Agano Kiravu
*Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
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Melanie S. S. Seabrook
*Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
‡Department of Immunology, University of Toronto, Toronto, Ontario, Canada;
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Berenice Alinde
*Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
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Susan P. Holmes
§Department of Statistic, Stanford University, Stanford, CA;
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Catherine A. Blish
¶Department of Medicine, School of Medicine, Stanford University, Stanford, CA;
‖Chan Zuckerberg Biohub, San Francisco, CA;
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Heather B. Jaspan
*Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
#Seattle Children’s Research Institute and Departments of Paediatrics and Global Health, University of Washington, Seattle, WA; and
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Clive M. Gray
*Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
**Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
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Key Points

  • Phenotypic differences exist between cord and birth peripheral blood CD4 cells.

  • Synchronous increase of Th17/Treg cells is disrupted by HIV/ART exposure.

  • Intrauterine HIV exposure was associated with a biomarker for epithelial gut damage.

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Abstract

Few studies have investigated immune cell ontogeny throughout the neonatal and early pediatric period, when there is often increased vulnerability to infections. In this study, we evaluated the dynamics of two critical T cell populations, T regulatory (Treg) cells and Th17 cells, over the first 36 wk of human life. First, we observed distinct CD4+ T cells phenotypes between cord blood and peripheral blood, collected within 12 h of birth, showing that cord blood is not a surrogate for newborn blood. Second, both Treg and Th17 cells expanded in a synchronous fashion over 36 wk of life. However, comparing infants exposed to HIV in utero, but remaining uninfected, with HIV-unexposed uninfected control infants, there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 wk. Focusing on birth events, we found that Treg cells coexpressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein, IL-7, and CCL20. This was in contrast with Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.

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Footnotes

  • This study was supported by the South African Medical Research Council Self-Initiated Research Grant and U.S. Department of Health and Human Services, National Institutes of Health Awards U01 AI131302 and R01 HD102050. S.D. was supported by a Claude Leon Fellowship.

  • The study was conceived and designed by S.D., C.A.B., H.B.J., and C.M.G. S.D., M.S.S.S., and A.K. designed flow cytometry and cell sorting experiments. B.A. and H.B.J. were responsible for participant enrollment, sample collection, and processing. Data generation and acquisition were performed by S.D. and analyzed by S.D., K.L., and S.P.H. S.D. drafted the original manuscript that was reviewed and edited by all authors.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    ART
    antiretroviral treatment
    ARV
    antiretroviral drug
    cART
    combined antiretroviral treatment
    FlowSOM
    Flow Self-Organizing Map
    GI
    gastrointestinal
    GLMM
    generalized linear mixed model
    iFABP
    intestinal fatty acid binding protein
    iHEU
    HIV-exposed uninfected infant
    iHEU-i
    infant born to HIV-infected woman who initiated cART during pregnancy at a median of 24.9 wk gestation
    iHEU-s
    infant born to HIV-infected woman who initiated cART before conception
    iHUU
    HIV-unexposed uninfected infant
    LV
    latent variable
    MDS
    multidimensional scaling
    PERMANOVA
    permutational multivariate ANOVA
    ROC
    receiver operating curve
    sPLS
    sparse partial least squares
    sPLS-DA
    sPLS discriminant analysis
    Treg
    T regulatory
    UMAP
    uniform manifold approximation and projection

  • Received June 3, 2021.
  • Accepted November 1, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (1)
The Journal of Immunology
Vol. 208, Issue 1
1 Jan 2022
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Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage
Sonwabile Dzanibe, Katie Lennard, Agano Kiravu, Melanie S. S. Seabrook, Berenice Alinde, Susan P. Holmes, Catherine A. Blish, Heather B. Jaspan, Clive M. Gray
The Journal of Immunology January 1, 2022, 208 (1) 27-37; DOI: 10.4049/jimmunol.2100503

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Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage
Sonwabile Dzanibe, Katie Lennard, Agano Kiravu, Melanie S. S. Seabrook, Berenice Alinde, Susan P. Holmes, Catherine A. Blish, Heather B. Jaspan, Clive M. Gray
The Journal of Immunology January 1, 2022, 208 (1) 27-37; DOI: 10.4049/jimmunol.2100503
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