High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells
Department of Pathology; Program in Molecular Medicine; Program in Bioinformatics and Integrative Biology; Division of Transfusion Medicine, Department of Medicine
Immunology and Infectious Disease
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.
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JCI Insight. 2017 Aug 3;2(15). pii: 93814. doi: 10.1172/jci.insight.93814. [Epub ahead of print]. Link to article on publisher's website
Falanga, Yves T.; Frascoli, Michela; Kaymaz, Yasin; Forconi, Catherine; Ong'echa, John Michael; Bailey, Jeffrey A.; Berg, Leslie J.; and Moormann, Ann M., "High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells" (2017). University of Massachusetts Medical School Faculty Publications. 1377.