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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Clinical Research and Public Health 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 5

PLZF+CD4+ T cells produce cytokines in response to both TCR-dependent and TCR-independent activation.

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PLZF+CD4+ T cells produce cytokines in response to both TCR-dependent an...
All T cell populations gated on live Vα7.2–CD4+TCR-αβ+ cells. (A and B) Frequencies of (A) IFN-γ+ and (B) TNF-α+ cells within indicated populations of CD4+ T cells of the SI and LI after stimulation with anti-CD3+ anti-CD28. (C–F) (C) Representative flow cytometry plots and frequencies of (D) IFN-γ+ and (E) TNF-α+ cells within indicated populations of SI CD4+ T cells after stimulation with anti-CD3+ anti-CD28 for 24 hours. (F) Frequencies of IFN-γ+ cells within indicated populations of intestinal TEM (left) and TCM (right) CD4+ T cells after stimulation with anti-CD3+ anti-CD28 for 24 hours. (G) Representative flow plots of intracellular Nur77 staining in intestinal CD4+ TEM cells after 4 hours of anti-CD3+ anti-CD28 stimulation. Mean frequency ± SD of gated populations (n = 7). (H) Frequencies of induced Nur77 expression within indicated populations of intestinal CD4+ TEM cells after 4 hours of anti-CD3+ anti-CD28 stimulation. Lines join paired samples. (I and J) Frequencies of (I) IFN-γ+ cells and (J) TNF-α+ among intestinal PLZF+ and PLZF–CD4+ T cells in response to cytokine stimulation with IL-12 plus IL-18 for 24 hours. (K) Frequencies of IFN-γ+ cells within PLZF+CD4+ T cells of the SI and thymus in response to cytokine stimulation with IL-12 plus IL-18 for 24 hours. Numbers in flow cytometry plots correspond to the mean ± SD of gated populations. Box plot whiskers span minimum and maximum; lines represent median. Circles represent individual donors. Kruskal-Wallis paired ANOVA with Dunn’s multiple comparison test (A, B, D, E, I), Mann-Whitney U test (K), and Wilcoxon’s matched-pairs signed rank test (F, H, J). *P < 0.05, **P < 0.01.