Preterm cord blood CD4+ T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4+ T cells in bronchopulmonary dysplasia

Abstract

Background Chorioamnionitis (CA) is associated with premature delivery and bronchopulmonary dysplasia (BPD). We hypothesize that preterm infants exposed to CA have reduced suppressive regulatory T cells (Treg) and increased non-regulatory T cell pro-inflammatory cytokines, increasing risk for BPD. Objective To evaluate cord blood CD4+ T cell regulatory phenotype and pro-inflammatory cytokine production in CA and BPD groups. Study Design Cord blood mononuclear cells from infants (GA ≤32 weeks), with or without placental histological evidence of CA (hChorio), were analyzed by flow cytometry. Clinical information was collected by retrospective chart review. Numbers of putative Treg (CD4+FoxP3+CD25+CD127Dim), CD4+ non-Tregs, and CD4+ T cell intracellular cytokine content following in vitro stimulation were compared with CA status and oxygen requirement at 36 weeks postmenstrual age. Result Absolute Treg numbers were not different in CA and non-CA exposed samples. However, the infants who developed BPD had a significant decrease in Treg and non-regulatory T cell numbers. Greater IL-6 production was observed in hCA group. Conclusion A pro-inflammatory CD4+ T cell status is noted in CA and BPD but the later disease is also associated with decrease in Tregs, suggesting that the development of BPD is marked by distinct inflammatory changes from those of CA exposed infants.

Flow-based sorting of neonatal lymphocyte populations for transcriptomics analysis

“…Our group and others have shown that alterations in the CD4+ T cell compartment are observed in infants who are born prior to term, in the presence of inflammatory conditions, or who develop the lung disease bronchopulmonary dysplasia (Misra et al, 2015; Rueda et al, 2015). Better understanding of prematurity-related alterations in the immune system associated with disease-specific pathophysiology could lead to identification of molecular markers for diseases of preterm infants and could reveal new targets for treating inflammatory respiratory disease (Misra, 2014).…”

MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

“…Moreover, following intrauterine inflammation, the fetal Th1/Th2 ratio shifts towards Th1 cells, with a corresponding increase in interferon-gamma (IFN-γ) [33]. Interestingly, several neonatal diseases are characterized by a pro-inflammatory state due to excessive pro-inflammatory lymphocyte subsets (Th1, Th17) and deficient representation in Tregs [34][35][36] (Table 1).…”

“…This confirms the notion that MSCs are most effective when administered in the context of inflammation. Accordingly, the combined administration of both ↑ in murine HI cerebral tissue [37] ↑ Th1 and Th17 in murine HI cerebral tissue [34] ↓ Treg in murine HI cerebral tissue [34] BPD ↓ M1 macrophages in murine lung [38] ↓M2 macrophages in murine lung [38] ↓ activated DCs in murine and human lung [39,40] Unchanged in murine lung [38] ↓ Th1 and Th17 in peripheral blood during the first week of life in BPD patients [41] ↓ Treg in cord blood in BPD patients [36] NEC ↓ M1 macrophages in murine NEC tissue [42] Unknown ↓ Th17 in human NEC tissue [35] ↓Treg in human NEC tissue [35] Periventricular leukomalacia (PVL), Hypoxic ischemic encephalopathy (HIE), Bronchopulmonary dysplasia (BPD), Necrotising enterocolitis (NEC), Lymphocytes T helper (Th), cerebrospinal fluid (CSF), Denditric cells (DCs), Hypoxia-ischemia (HI)…”

“…Increased protein levels and high mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8) have been demonstrated in airway secretions of infants with developing BPD [98]. Decreased number of Tregs in the cord blood [36] and higher proportions of activated T cells in the peripheral blood during the first week of life [41] can predict the development of BPD. In experimental BPD, macrophages were polarized towards the M1 phenotype, while the M2 phenotype was inhibited [38] (Table 1).…”

Affect of Early Life Oxygen Exposure on Proper Lung Development and Response to Respiratory Viral Infections

“…Given the surprising finding that cord blood contains T cells with an activated/memory phenotype, it is possible that these cells are poised to contribute to inflammatory lung disease (147). Recent work has also reported decreased CD4 T cells in cord blood from preterm infants who develop moderate BPD (148). Despite the finding that cytotoxic T cell function is not altered in mice exposed to hyperoxia followed by IAV infection (106), it is possible that CD4 T cells play a role in hyperoxia-mediated lung damage in humans and in the development of disease later in life.…”