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.
Visual Abstract
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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