High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells
Yves T. Falanga, Michela Frascoli, Yasin Kaymaz, Catherine Forconi, John Michael Ong’echa, Jeffrey A. Bailey, Leslie J. Berg, Ann M. Moormann
Yves T. Falanga, Michela Frascoli, Yasin Kaymaz, Catherine Forconi, John Michael Ong’echa, Jeffrey A. Bailey, Leslie J. Berg, Ann M. Moormann
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Research Article Immunology Infectious disease

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Abstract

Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4+ and CD8+ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8dim T cells with an innate-like profile (Granzyme Bhi, IFNγlow, TNFαlow, PLFZhi, ID2hi, IKZF2hi) in contrast to age-matched children residing in a low pathogen–exposure area who display a more conventional CD8bright profile (IFNγ+, TNFα+, CCL4+). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses.

Authors

Yves T. Falanga, Michela Frascoli, Yasin Kaymaz, Catherine Forconi, John Michael Ong’echa, Jeffrey A. Bailey, Leslie J. Berg, Ann M. Moormann

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Figure 1

Children with elevated pathogen burden exhibit a distinct CD8+ T cell immune profile.

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Children with elevated pathogen burden exhibit a distinct CD8+ T cell im...
(A) Schematic diagram summarizing the study design: peripheral blood mononuclear cells (PBMCs) were collected from Kenyan children residing in Kisumu (high malaria burden) and Nandi (low malaria burden) at ~2.5 years of age and at ~6.5 years of age. (B) Isolated PBMCs were stained with antibodies and analyzed by flow cytometry. Depicted is a representative t-distributed stochastic neighbor embedding (t-SNE) plot generated by ACCENSE after dimensionality reduction and unsupervised clustering of flow cytometry data on unstimulated cells. Main image: cluster numbers (defined by markers combination and expression level; dots of identical colors belong to the same cluster). Right panel: representative t-SNE plot of CD8+ T cell clusters displaying CD3+ CD8bright and CD8dim cells identified as clusters 29, 40, 41, and 55. Images below: representative heatmaps depicting the expression level of each marker and spatial localization on the t-SNE map. (C) Megacluster image of flow cytometry data performed by PhenoGraph showing malaria burden and CD8 surface expression (mean fluorescence intensity [MFI] scale) on a population level. Displayed here are unstimulated PBMC vials from school-age children living in Nandi (orange) and Kisumu (purple). Each dot represents a cluster, and the size of the dot represents the frequency of cells in the cluster. Surface CD8 expression (MFI) is displayed on heatmap scale on the right. Image generated from 5 independent experiments.