CD161 contributes to prenatal immune suppression of IFN-γ-producing PLZF⁺ T cells

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

¹Division of Neonatology, Department of Pediatrics, and ²Biomedical Sciences Program, UCSF, San Francisco, California, USA. ³Maternal and Fetal Medicine Department, Institute for Women's Health, University College London, London, United Kingdom. ⁴Institute for Computational Health Sciences, UCSF, San Francisco, California, USA. ⁵Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA. ⁶Division of Infection Immunity and Inflammation, University College London Great Ormond Street Institute of Child Health, London, United Kingdom. ⁷Department of Surgery, UCSF, San Francisco, California, USA.

Address correspondence to: Joanna Halkias, Division of Neonatology, Department of Pediatrics, University of California San Francisco, 550 16th Street, Box 0734, San Francisco, California 94143, USA. Phone: 415.502.2526; Email: [email protected].

Received December 20, 2018; accepted May 28, 2019

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information:J Clin Invest. 2019;129(9):3562–3577.https://doi.org/10.1172/JCI125957.

Journal of Clinical Investigation 129(9):p 3562-3577, September 2019. | DOI: 10.1172/JCI125957

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.