Regulation of thymic immune development by intestinal microbes in early life
Newborns face unique immunological challenges immediately after birth. As they depart a relatively sterile fetal environment, they are abruptly exposed to a multitude of foreign antigens, the major burden of which is in the form of the microbiota newly colonizing the gastrointestinal tract. These rapidly multiplying foreign invaders represent, by far, the biggest threat to the neonatal immune system, which has to recognize and classify these organisms as benign, commensal or pathogenic.
Research has shown that effective communication between early microbes and mucosal immune cells is essential to the formation of healthy microbial communities and promotion of a well-functioning immune system.
The cells of the immune system that participate in mucosal immunity develop in an organ called the thymus located under the breastbone above the heart.
Until now, it has been unclear if intestinal microbes influence the development of these cells in the thymus in early life.
Researchers at the Mucosal and Immunology Biology Research Center ( MIBRC ) at Massachusetts General Hospital have reported that gut microbes regulate the development of specialized immune cells in the thymus that play a critical role in mucosal tolerance.
The findings of their extensive research were published in Proceedings of the National Academy of Science ( PNAS ), USA.
Researchers focused on a subset of immune cells that express the transcription factor PLZF. These cells, collectively called innate and innate-like lymphocytes, typically function at the gut mucosal barrier interface and provide immune protection at mucosal sites.
To study the development of these immune cells in the context of gut microbes, researchers monocolonized germ-free mice with a model human commensal, Bacteroides fragilis, and demonstrated that this single species of bacteria could restore the development of PLZF+ innate and innate-like lymphocytes in the thymus of infant mice.
In further proof-of-concept studies, they showed that a mutant B. fragilis lacking expression of Polysaccharide A ( PSA ) was unable to do the same, suggesting that specific microbial antigens could regulate this early life developmental process.
A similar deficit in these cells was observed in mutant mice that lacked the expression of Toll like receptor 2, a receptor that recognizes bacteria and bacterial components, including Bacteroides fragilis PSA, to initiate host protective immune responses.
To understand how this microbial message was delivered to developing thymic cells, researchers used a novel mouse model to track the migration of cells from the colon to the thymus.
Researchers showed that a class of antigen-presenting cells called plasmacytoid dendritic cells ( pDCs ) are imprinted by intestinal microbes and migrate from the gut to the thymus in early life to regulate the development of thymic lymphocytes.
The unbalanced development of an infant's gut microbiome is thought to play a role in disease development later in life.
Disturbing the microbiota in infancy by antibiotics or diet, for example, has been linked to increased risk of allergies, asthma and autoimmune disorders including celiac disease and inflammatory bowel disease ( IBD ).
Researchers have shown that thymic PLZF+ cells did not develop efficiently in mice treated with broad-spectrum antibiotics in early life, but mice treated in later life were spared.
The study has also shown that microbe-induced altered development of thymic innate and innate-like cells in early life persists into adulthood and leads to increased susceptibility to experimental colitis.
Importantly, disease severity could be moderated by the transfer of PLZF+ cells from mice that developed with normal microbiota in early life. ( Xagena )
Source: Massachusetts General Hospital, 2020
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