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 shows that effective “crosstalk” or 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. Now, researchers at the Mucosal and Immunology Biology Research Center (MIBRC) at Massachusetts General Hospital report that gut microbes regulate the development of specialized immune cells in the thymus, that play a critical role in future mucosal tolerance.
The findings of their extensive research were published in Proceedings of the National Academy of Science USA last week. Nitya Jain, PhD, and colleagues focused their studies 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. Nearly all hematopoietic cells mature in the bone marrow. In contrast, the cells destined to be T cells leave the bone marrow as multipotent progenitors and home to the thymus where signals from stromal cells are required for commitment to the T cell lineage. Once directed into the T lineage, the cells undergo a rigorous selection process that eliminates more than 95% of the candidate T cells. 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,
This is 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 polysaccharide PSA, to initiate host protective immune responses. To understand how this microbial message was delivered to developing thymic cells, the team used a novel mouse model to track the migration of cells from the colon to the thymus. The photo-conversion strategy was developed at the Wellman Center for Photomedicine, in 2018. 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).
The team demonstrates one mechanistic basis for this observation. They show 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. This has sharp and undeniable implications for the neonatology and pediatrics. Additionally, the study shows 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. Dr Jain Explained: “There appeared to be an early-life time window when developing immune cells in the thymus were particularly susceptible to microbial influence. For the first time, we have revealed “a novel communication between intestinal microbes and developing cells in the thymus. It shapes the immune ‘repertoire’ in early life and affects how the host will respond to disease throughout the lifespan. This has significant implications for the design of strategies to treat autoimmune disorders such as IBD. Our studies point to a previously unexplored pathway that may be developed as an adoptive cell therapy for patients.”
Her chief MIBRC Director Alessio Fasano, MD, concluded: “How we ‘choose’ our ideal microbiome to teach our immune system to defend us, rather than harm us, is still a big question mark. For the first time we have shed light on the very early mechanisms that are in charge of establishing a healthy relationship between these two systems”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Ennamorati M et al., Jain N. Proc Natl Acad Sci USA. 2020 Jan 21.
Miranda-Ribera A et al. Front Immunol. 2019 Sep 19; 10:2233.
Caio G et al., Fasano A. BMC Medicine 2019 Jul 23; 17(1):142.