The immune development of offspring is, in part, controlled by cues from the mother. However, little is known about how white blood cells regulate offspring immunity. Now, a new study uncovers that maternal innate-like lymphocytes (specifically γδ T cells) influence the transfer of maternal microbiota during birth and nursing, and impact the lung immune response in newborns.

The researchers found that maternal γδ T cells, which were never associated with this process, are involved in the development of the newborns’ lung immunity by exerting an effect on the gut microorganism’s colonization.

This work is published in Cell Reports in the paper, “Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.

Before birth, the lungs are filled with a sterile liquid that is replaced by gas in the first breath after birth. This causes an immune reaction involving substantial lung tissue remodeling, called “first breath response.” Now, researchers at Instituto de Medicina Molecular João Lobo Antunes (iMM) at the Universidade de Lisboa, in Lisbon, Portugal, have implicated the γδ T cells in this immune response in mice.

“We found that newborns born and raised by mothers lacking γδ T cells acquire a different gut microbiota. The intestinal microorganisms in these mice are not able to produce sufficient amounts of a type of molecules that are important to modulate the lung immune response to the first breath,” explained Bruno Silva Santos, PhD, group leader and vice director at the iMM, adding: “As a result, these pups have an exacerbated first breath immune response.”

More specifically, the authors noted that the pulmonary milieu of the mice born from the TCRδ−/− dams was “selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams.”

The type of immune response that is induced after the first breath is also relevant in other contexts. The researchers observed a similar pattern in the progeny of mothers lacking γδ T cells in response to an infection by a parasite that induces lung damage.

Upon infection, the mice born from the TCRδ−/− moms (independent of their own genotype) had an increased type 2 inflammatory response, a distinct intestinal microbiota (acquired during birth and fostering) and less intestinal short-chain fatty acids.

The authors added that adding exogenous short-chain fatty acids suppressed the first-breath- and infection-induced inflammation.

“We saw that either antibiotic treatment to kill the microorganisms in the gut, or supplementation with short-chain fatty acids, the molecules that are down in mice with exacerbated immune responses, abolish the differences between mice born from mothers with and without these immune cells,” added Pedro Papotto, PhD, currently a post-doc in the lab of Judi Allen, PhD, professor, University of Manchester, U.K. “This shows that the effects observed in the pups are indirect and linked to these molecules produced by the microbiota.”

The work introduces another level of complexity to the transfer of microbiota from mothers to newborns. “We found that the transfer of microorganisms from mothers is not restricted to the process of birth. If pups born from mothers lacking γδ T lymphocytes are raised with mothers that have these cells, their immune response is restored,” explained Papotto. ”In fact, our study suggests that the majority of the bacterial communities must be transferred after birth, during nursing.”

Graphical abstract, Papotto et al.
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