Breast milk is not just nutrition; it’s an immune delivery system, passing along cells, cytokines, and antibodies that protect the newborn and begin to train their immune system. Prior studies on maternal antibody-mediated immune instruction have focused on a type of antibodies called immunoglobulin A (IgA), which coat gut pathogens and other microbes to neutralize them and prevent invasion. But beyond IgA, breast milk contains other antibody types (like IgG) that defend the body in distinct ways. However, the mechanisms by which maternal IgG shapes neonatal immune responses to gut antigens has remained a mystery.
Recent work led by scientist Dr. Meera Shenoy in the laboratory of Meghan Koch in the Basic Sciences Division at Fred Hutch investigated these processes in depth. The authors’ study, recently published in Science, used a specialized mouse model that allowed for precise control over antibody exposure, timing, and gut microbial environment to define how breast milk IgG shapes mucosal immunity in early life.
To control which antibodies the pups received, the researchers used mothers with genetic deletion of essential parts of the antibody, the mu heavy chain gene (μMT−/−) or JH gene segments (Jh−/−), and orally supplemented purified IgG or IgA to the offspring. To control timing of antibody passage, they either fed pups at different times or cross-fostered pups at different ages, and to control the microbial environment, they utilized conventional versus germ-free housing.
They discovered that pups that did not receive breast milk antibodies during the first week of life exhibited immune dysregulation, characterized by increased germinal center T follicular helper (GC TFH) cells in gut-associated lymphoid tissues. GC TFH cells “coach” B cells inside lymph nodes on antibody production. Thus, breast milk prevented overactive adaptive immune responses by restraining excessive GC TFH activity. This early exposure coincided with a natural period of heightened intestinal permeability, allowing IgG to cross the gut barrier and interact directly with immune cells. Purified IgG, but not IgA or IgM, reproduced this protective effect even at low doses, pinning down that the effects can be attributed to breast milk IgG.
Through a specialized flow cytometry technique, the researchers found that breast milk IgG bound strongly to neonatal gut bacteria, particularly IgG2b and IgG3 subclasses, forming immune complexes that can engage neonatal Fc receptors and complement pathways—immune sensing systems that trigger downstream responses. Using pups deficient in these sensing systems (FcRγ−/−, C1qa−/−, and double mutants), the authors showed that IgG signals through both Fc receptors and complement to regulate immune activation. Germ-free and antibiotic-treated pups confirmed that the immunoregulatory effect depended on microbial antigens: without these antigens, maternal antibody deficiency no longer produced exaggerated TFH responses.
Importantly, outcomes extended beyond immune cell counts. Oral IgG supplementation during the first week of infancy reduced susceptibility to chemically induced colitis (colon inflammation) at weaning. In a dietary tolerance model, pups lacking maternal antibodies developed heightened TFH and IgE responses to the model food antigen ovalbumin, while early IgG feeding prevented these allergic-type reactions, even though the administered IgG was not specific to the dietary antigen. This demonstrated that maternal IgG promotes tolerance broadly, not just to individual antigens.
“Mothers transmit IgG antibodies through breastfeeding, which bind to bacteria in the infant gut in early life and dampen intestinal immune responses to the gut microbiota weeks later, following weaning. Surprisingly, milk IgG also suppressed allergic responses to dietary antigens never-before-encountered by the mother or offspring, indicating a broad function for milk IgG in shaping healthy immune responses to the microbiota and food.” Principal investigator Dr. Meghan Koch explains.
The authors emphasize that while mouse milk contains proportionally more IgG than human milk, the principle that maternal antibodies directly program neonatal immune cells could be conserved. Maternal IgG doesn’t just passively protect infants; it actively instructs their immune systems. By binding with neonatal gut microbes in early life, IgG calibrates gut immune responses and promotes tolerance to both microbial and food antigens that are introduced later.
Dr. Koch considers the implications of this work. “A little goes a long way: Even brief exposure to small amounts of milk IgG antibodies early in life markedly dampened infants’ immune responses to harmless food- and microbiota-derived antigens. These findings suggest that supplementing formula with IgG could be both effective and feasible—since only minimal quantities may be required—and that even a few days of breastfeeding could have meaningful benefits for infants.”
This exciting study highlights potential new approaches to boost healthy immune programming in early life and may offer insight into autoimmune and inflammatory disorders established in early immune development.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Meghan Koch contributed to this research.
The spotlighted research was funded by Fred Hutchinson Cancer Center’s Immunotherapy Integrated Research Center Award, the Washington Research Foundation, the Pew Charitable Trusts, the National Institutes of Health, the Hartwell Foundation, the Rita Allen Foundation, Fred Hutchinson Cancer Center’s Microbiome Research Initiative and the Kenneth Rainin Foundation.
Shenoy MK, Rico D, Lorant A, Toure H, Gordon S, Milburn L, Schwensen J, Caban M, Koch M. 2025. Breast milk IgG engages the mouse neonatal immune system to instruct responses to gut antigens. Science. DOI:10.1126/science.ado5294
Science Spotlight writer Kelly Mitchell is a postdoctoral fellow in the Paddison Lab at Fred Hutch Cancer Center. She utilizes live cell reporters and CRISPR screening to study how glioblastoma cancer cells resist chemotherapy and radiation treatment. She obtained her PhD in cellular biology from Albert Einstein College of Medicine.
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