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 September 3, 2019; First published May 30, 2019
Citation Information: J Clin Invest. 2019;129(9):3562-3577. https://doi.org/10.1172/JCI125957.
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Clinical Medicine Development Immunology

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 1

PLZF+Vα7.2–CD4+TCR-αβ+ T cells are highly abundant in the fetal intestine.

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PLZF+Vα7.2–CD4+TCR-αβ+ T cells are highly abundant in the fetal intestin...
(A) Representative flow plots of sequential gating strategy for the identification of intestinal memory T cells indicating the proportion of fetal intestinal effector memory (CD45RO+CD45RA–CCR7–) CD4+TCR-αβ+ T cells that express PLZF and CD161. (B) Frequencies of PLZF+ and PLZF– cells among effector memory CD4+TCR-αβ+ T cells of the fetal SI. (C) Representative imaging of PLZF expression among CD3+CD4+ T cells in tissue sections of the SI (n = 3). Arrowheads indicate triple-positive cells. Scale bar: 50 mm. Original magnification, ×400. (D) Representative flow plots of PLZF and CD161 expression among Vα7.2–CD4+TCR-αβ+ T cells in fetal tissues. (E) Frequencies of PLZF+Vα7.2–CD4+TCR-αβ+ T cells and (F) proportion of CD161+ cells among PLZF+Vα7.2–CD4+TCR-αβ+ T cells in fetal tissues. MLN, mesenteric lymph node; Spl., spleen; Liv., liver; Lu, lung. (G) Association between frequencies of intestinal PLZF+Vα7.2–CD4+TCR-αβ+ T cells and gestational age (GA), Spearman’s rank correlation. Numbers in flow cytometry plots correspond to the mean ± SD of gated populations. Circles represent individual donors. Box plot whiskers span minimum and maximum; lines represent median. **P < 0.01; ***P < 0.001; ****P < 0.0001, Wilcoxon’s matched-pairs signed rank test (B), Kruskal-Wallis paired ANOVA with Dunn’s multiple comparison test (E and F).