Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection

Abstract

Immature mucosal defenses contribute to increased susceptibility of newborn infants to pathogens. Sparse knowledge of age-dependent changes in mucosal immunity has hampered improvements in neonatal morbidity due to infections. Here, we report that exposure of neonatal mice to commensal bacteria immediately after birth is required for a robust host defense against bacterial pneumonia, the leading cause of death in newborn infants. This crucial window was characterized by an abrupt influx of interleukin (IL)-22 producing group 3 innate lymphoid cells (IL22+ILC3) into the lungs of newborn mice. This influx was dependent on sensing of commensal bacteria by intestinal mucosal dendritic cells. Disruption of postnatal commensal colonization or selective depletion of dendritic cells interrupted the migratory program of lung IL-22+ILC3 and made the newborn mice more susceptible to pneumonia, which was reversed by transfer of commensal bacteria after birth. Thus, the resistance of newborn mice to pneumonia relied on commensal bacteria-directed ILC3-influx into the lungs, which mediated IL-22-dependent host resistance to pneumonia during this developmental window. These data establish that postnatal colonization by intestinal commensal bacteria is pivotal in the development of lung defenses in mice.

Innate Immunity to Respiratory Infection in Early Life

“…Colonization by the microbiota in neonates protects against the accumulation of potentially pro-inflammatory mucosal iNKT cells in the lung and gut (110). Colonization of the gut of neonatal mice can also lead to intestinal DC mediated upregulation of CCR4 on IL-22 producing ILC3, which allows their migration into the lungs of neonatal mice, and promotes protection against bacterial pneumonia (111).…”

“…Additionally, commensal bacteria may influence neonatal respiratory immunity indirectly. For example, sensing of commensal bacteria by gut DCs promotes resistance to bacterial pneumonia in neonatal mice (111). Factors that shape the microbiota, such as delivery by cesarean section and antibiotic use in early life and pregnancy, are likely to profoundly influence the developing immune system (14,135).…”

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…109 Furthermore, changes in the microbiota of one mucosal tissue can impact the frequency and function of immune cells of other mucosal tissues. 110 On the other hand, the impact of the microbiota is not limited to the mucosal surfaces and can influence apparently any part of the body, including seemingly remote areas, such as the brain. 111 With regard to iNKT cells, the above-mentioned systemic effects of antibiotic treatment and the role of iNKT cells are relevant in sepsis, 112 which is often caused by translocated intestinal bacteria.…”

Compartmentalization of intestinal bacteria by hepatic ILC3s prevents infections after surgery

“…In the intestine, barriers that limit the penetration of commensal and pathogenic microbes (8) consist of mucus, immunoglobulins, antimicrobial peptides, epithelial cells and immune cells (9). In particular, type 3 innate lymphoid cells (ILC3s), which are constitutively present at barrier sites and depend on the transcription factor Rorγt for their differentiation and function, play a pivotal role in host-microbial compartmentalization in the intestine and lung (10,11). ILC3s have the specialized capability to sense both host-derived and environmental signals and can integrate and relay the cues to other cells through cytokine secretion or cell-cell interactions (12).…”