CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells
Joanna Halkias, … , Tippi C. MacKenzie, Trevor D. Burt
Joanna Halkias, … , Tippi C. MacKenzie, Trevor D. Burt
Published May 30, 2019
Citation Information: J Clin Invest. 2019;129(9):3562-3577. https://doi.org/10.1172/JCI125957.
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CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells

Abstract

BACKGROUND While the human fetal immune system defaults to a program of tolerance, there is a concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response, with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown.METHODS We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with proinflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared with that of healthy term controls.RESULTS We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor promyelocytic leukemia zinc finger (PLZF). PLZF+CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced proinflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFN-γ in a fetal-specific manner. IFN-γ–producing PLZF+CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation.CONCLUSION Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.FUNDING This work was supported by the UCSF Clinical and Translational Science Institute (CTSI) Pilot Award for Basic and Translational Investigators (2014908), UCSF (K12HD072222), the NIAID (K08 AI128007 and 1F31AI136336-01), a National Science Foundation (NSF) Graduate Research Fellowship (1650113 ), and an Academy for Medical Sciences Clinical Lecturer grant (535274).

Authors

Joanna Halkias, Elze Rackaityte, Sara L. Hillman, Dvir Aran, Ventura F. Mendoza, Lucy R. Marshall, Tippi C. MacKenzie, Trevor D. Burt

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Figure 3

PLZF+CD4+ T cells are a transcriptionally distinct population of intestinal T cells.

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PLZF+CD4+ T cells are a transcriptionally distinct population of intesti...
(A) PCA of the top 1000 variable genes identified by RNA-Seq of fetal intestinal PLZF+CD4+ T cells (n = 5), PLZF–CD4+ T cells (n = 4), and Vα7.2+CD161+ T cells (n = 5). Ellipses denote the 95% confidence intervals of population means (PERMANOVA R2 0.92, P < 0.001). Box plots indicate scores for PC1 (bottom) and PC2 (right). (B) Numbers of genes with more than 2-fold (FDR < 0.05) increase (red) or decrease (white) in expression levels between populations. (C) DE genes (>2 fold, FDR < 0.05) in PLZF+CD4+ T cells compared with Vα7.2+CD161+ T cells. DE genes (dark grey), TCR genes, enriched (orange) or diminished (purple), in PLZF+CD4+ T cells are labeled. (D) Frequencies (mean ± SEM) of expression of 21 TCR-Vβ chains by flow cytometry in fetal intestinal PLZF+CD4+ T cells (red) compared with PLZF–CD4+ T cells (white). Circles indicate individual donors. (E) Heatmap shows color-coded relative enrichment of cluster 1 DE genes in PLZF+CD4+ T cells relative to PLZF–CD4+ T cells among indicated cell types identified by correlation analysis using the Human Primary Cell Atlas. Box indicates lymphoid-enriched genes associated with immune activation. (F) Multi-way comparison of DE genes (>2 fold, FDR < 0.05) in PLZF+CD4+ T cells compared with Vα7.2+CD161+ T cells (y axis) and compared with PLZF–CD4+ T cells (x axis) identifies a core signature of genes uniquely enriched (red) and diminished (blue) within intestinal PLZF+CD4+ T cells. Selected genes involved in immune response, immune regulation, and leukocyte migration are labeled.