Altered distributions and functions of natural killer T cells and γδ T cells in neonates with neonatal encephalopathy, in school-age children at follow-up, and in children with cerebral palsy

Abstract

We enumerated conventional and innate lymphocyte populations in neonates with neonatal encephalopathy (NE), school-age children post-NE, children with cerebral palsy and age-matched controls. Using flow cytometry, we demonstrate alterations in circulating T, B and natural killer cell numbers. Invariant natural killer T cell and Vδ2 + γδ T cell numbers and frequencies were strikingly higher in neonates with NE, children post-NE and children with cerebral palsy compared to age-matched controls, whereas mucosal-associated invariant T cells and Vδ1 T cells were depleted from children with cerebral palsy. Upon stimulation ex vivo, T cells, natural killer cells and Vδ2 T cells from neonates with NE more readily produced inflammatory cytokines than their counterparts from healthy neonates, suggesting that they were previously primed or activated. Thus, innate and conventional lymphocytes are numerically and functionally altered in neonates with NE and these changes may persist into school-age.

The role of lymphocytes in neonatal encephalopathy

“…Neonatal B cells lack antigenic exposure, furthermore they have impaired antibody production and an incomplete surface immunoglobulin repertoire ( Li et al., 2017 ). Our group reported that circulating B cell numbers are higher in neonates and school-age children with NE and cerebral palsy compared to age-matched control subjects ( Taher et al., 2021 ). B cell frequencies are higher in the injured hemisphere of the brain compared to the uninjured hemisphere 7 days after HI in a mouse model of HI-induced preterm brain injury, whereas T cells are found as soon as 3 days after HI ( Nazmi et al., 2018 ).…”

“…observed that inactivation of NK cells by CD161 knockdown resulted in a decrease in brain and systemic organ atrophy and neurobehavioral deficits ( Fathali et al., 2013 ), suggesting a key role for NK cells in brain injury and multiorgan dysfunction in NE. Investigating human peripheral blood cell phenotypes, Taher and co-workers ( Taher et al., 2021 ) found that circulating NK cell frequencies are higher in neonates with NE compared to healthy neonates and these cells displayed activated phenotypes and more readily produced IFN-γ, TNF-α and granzyme B upon stimulation ex vivo .…”

“…reported an increase in TNF-α, IL-1β, IL-6, IL-10 and memory CD45RO + T cells in cord blood and suggested this as a biomarker to predict cerebral lesions soon after delivery in preterm infants ( Duggan et al., 2001 ). We reported that circulating T cell numbers are similar in neonates with NE and in healthy neonates but the T cells from neonates with NE more readily produced inflammatory cytokines (IFN-γ, TNF-α and IL-17) and the cytotoxic mediator granzyme B, suggesting that they are primed or activated in vivo ( Taher et al., 2021 ). T cell numbers were higher in patients with cerebral palsy compared to control subjects.…”

“…We used flow cytometry to investigate the numbers and functions of circulating γδ T cell subsets in a large cohort of neonates with NE, school-age children with a history of NE but who were clinically stable at the time of study, and children with cerebral palsy ( Taher et al., 2021 ). We found striking increases in the frequencies and numbers of the Vδ2 subset of γδ T cells in neonates and school-age children with NE and cerebral palsy compared to age-matched healthy donors, whereas Vδ1 T cells were depleted from children with cerebral palsy.…”

“… Mediators and transcription factors Stage of the disease Release Effect HIF-1α Early stages Hypoxia Neuroprotection ( Bustelo et al., 2020 ) STAT3/JAK2 Early stages Hypoxia Neurodegeneration ( Hristova, 2017 ) ATF-6 and caspase-3 Early stages Hypoxia Neurodegeneration ( Liu et al., 2015 ) CCL2, CCL3, CCL4, CCL5, CXCL1 and CXCL10 CXCL12, MIP-1α and MIP-1β, CCL5, CCL21 and CCR6. Early stages Macrophages Astroglia Microglia Mast cells Neurodegeneration ( Hagberg et al., 2015 ) GM-CSF, IL-8, IL-1β, IL-6, IL-10, TNF-α and VEGF Early stages Macrophages Astroglia Microglia Mast cells Neurodefeneration ( O'Hare et al., 2017 ) IFN-γ, TNF- α, granzyme B, IL-6, IL-4, IL-12, IL-17 Early and later stages in the disease NK cell T cells Vδ2 T cells Pro-inflammatory ( Taher et al., 2021 ) IL-10 Later in the disease B cells Anti-inflammatory ( Bodhankar et al., 2013 ) IL-18, TGF-β Later in the disease NK cells T cells Chronic inflammation ( Zareen et al., 2020 ) …”