Neonatal lung immune responses show a shift of cytokines and transcription factors toward Th2 and a deficit in conventional and plasmacytoid dendritic cells

Abstract

The high incidence of lung-damaging life-threatening respiratory infections in infants may be related to the immaturity of their immune systems. To determine whether lung immune features differ in early life compared with those in adulthood, whole lung as well as lung T lymphocyte and DC responses were investigated in BALB/c neonates versus adults. Higher expression of GATA-3 and rapid and sustained production of type 2 cytokines by lung explants after in vitro exposure to anti-CD3 was the hallmark of the neonatal period, suggestive of a Th2 bias. Neonatal lung GATA-3-producing cells were identified as CD3 1 , CD4 and CD8 double-negative T lymphocytes, a subset found at a higher frequency in neonatal than adult lung. The neonatal lungs contained fewer conventional DCs, with a lower ratio of CD103 1 to CD11b 1 DCs, and a much lower number of plasmacytoid DCs in comparison with adult lungs. Yet, when stimulated in vivo by BCG, neonatal lung DCs matured and primed adult naïve CD4 1 T cells toward Th1 as efficiently as adult BCG-primed lung DCs. Conversely, both adult and neonatal BCG-primed lung DCs induced a Th2 cytokine response from neonatal naïve lymph node T cells, suggestive of an intrinsic feature of neonatal T lymphocytes.

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

“…(legend continued on next page) ( Figure 3A). A small number of studies have described increased numbers of CD11b + DCs in neonatal lungs (Gollwitzer et al, 2014;Roux et al, 2011), but a careful distinction between CD11b + cDCs and moDCs has never been made. Using a panel that discriminates cDCs from monocyte-derived DCs , we found that CD11b + CD64 + moDCs represented the largest DC subset in the lung from E20 until PND2 ( Figure 3B).…”

“…In support, the spontaneous wave of type 2 immunity around PND14 was intact in Rag2-deficient mice, and ILC2 accumulations were even enhanced in these mice, most likely due to increased availability of IL-2 in Rag2 À/À mice. Studies in neonatal rodents and humans reported scarcity as well as immaturity of pulmonary DCs, hyporesponsiveness to PAMPs, and low lymphocyte numbers and therefore suggested incompetence of the early postnatal pulmonary immune system to mount adaptive immune responses, an effect that was even exacerbated in germ-free mice (Belderbos et al, 2009;Gollwitzer et al, 2014;Nelson and Holt, 1995;Nelson et al, 1994;Roux et al, 2011;Tschernig et al, 2006). In accordance with these studies, we found that DCs were indeed severely impaired in neonatal lungs, and the few CD11b + DCs in neonatal lungs during the first post-natal week were sessile CD11b + CD64 + moDCs that closely resemble macrophages Plantinga et al, 2013).…”

Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection

“…The neonatal immune response (1), and in particular the immune response in the lung (24), is Th2 skewed. We have developed a mouse model of the delayed sequelae of early-life RSV infection (4), and using this model, we have previously shown that altering the T helper balance away from Th2 using recombinant viruses that express cytokines can reduce the disease outcome (13).…”

“…We have developed a mouse model of the delayed sequelae of early-life RSV infection (4), and using this model, we have previously shown that altering the T helper balance away from Th2 using recombinant viruses that express cytokines can reduce the disease outcome (13). One factor influencing neonatal Th2 skewing is antigenpresenting cell (APC) immaturity; there are fewer APCs in neonatal lungs (24), and they are severely deficient in major histocompatibility complex class II (MHCII) and costimulatory molecule expression (including CD40, CD80, and CD86) and exhibit reduced interleukin-12 (IL-12) production (9). The insufficient IL-12 responses and the low MHC peptide density (favoring priming of Th2-type responses [20]) may limit the Th1 response in neonates and hence lead to Th2 skewing (2).…”

“…Exposure to ligands of the Toll-like receptor (TLR) family of pattern recognition receptors can induce accelerated maturation of APCs, switching the response away from Th2 toward a protective Th1 response (24), which can be protective against the development of allergy (19). Evidence from cohorts of farm children have shown that increased exposure to lipopolysaccharide (LPS) is a protective factor against allergy (7).…”