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

• Published in: The Journal of clinical investigation 2019-09, Vol.130 (9), p.3562-3577
• Main Authors: Halkias, Joanna, Rackaityte, Elze, Hillman, Sara L, Aran, Dvir, Mendoza, Ventura F, Marshall, Lucy R, MacKenzie, Tippi C, Burt, Trevor D
• Format: Article
• Language: English
• Subjects: Bioinformatics; Biomedical research; Birth; CD4 antigen; Cell activation; Clinical Medicine; Cord blood; Cytokines; Effector cells; Fetuses; Genomes; Genotype & phenotype; Immune system; Immunological tolerance; Infants; Inflammation; Intestine; Lectins; Leukemia; Lymphocytes; Lymphocytes T; Memory cells; Mucosa; Neonates; Phenotypes; Pregnancy; Premature birth; Promyeloid leukemia; T cell receptors; Transcription factors; Translation; Zinc finger proteins; γ-Interferon
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI125957

While the human fetal immune system defaults to a program of tolerance, there is 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. We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory 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 to healthy term controls. 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 pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-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. Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.