Regulation of hepatic and systemic immune responses

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Over millions of years the microbiota of mammals co-evolved with their hosts, resulting in a symbiotic host-microbe relationship that is critical to host physiology. At all phases of life, the microbiota and the host immune response shape each other. However, conventional laboratory mice are lacking many of the microbes and pathogens that have co-evolved with mammals in the natural world. To mitigate this problem, we previously established mouse models that combined the tractable genetics of C57BL/6 mice with the natural microbiota (bacteria, viruses, fungi, mites and protozoa) of wild mice. This was achieved by transferring embryos from conventional C57/BL6 mice into pseudopregnant wild mice. We reported that these mice serve as better models for human responses than conventional laboratory mice in two preclinical studies (Science 2019, PMID: 31371577). The offspring were used to generate a mouse colony that is now maintained for more than 5 years. In FY’25, we completed an in-depth prospective analysis of microbiota and immune responses of the C57BL/6 mouse colony with natural microbiota, symbionts and pathogens (Wildling colony). We reported an increased richness and alpha-diversity of the wild-derived bacterial microbiota with greater stability and resilience over time than those of conventional laboratory mice (Immunity 2025, PMID 40730165). In contrast, the gut the mycobiome of Wildling mice had reduced a-diversity compared to that of conventional laboratory mice, with a dominant fungus, Kazachstania pintolopesii. We contributed to a collaborative study with Dr. Iliev’s laboratory at NYU, which demonstrated that this fungal symbiont induced type-2 immune responses that induce resistance against helminths (Nature 2024, PMID 39604728). The presence of natural microbiota, symbionts and pathogens in the Wildling colony increased the number of immune cells across organs, particularly those of myeloid cell populations, in comparison to those in conventional laboratory mice. This differential immune cell expansion was primarily driven by increased numbers of eosinophils, neutrophils and monocytes. In contrast, the lymphoid cell population in the spleens of Wildling mice were of equal size or – in females – smaller size than its counterpart in conventional laboratory mice. This effect was primarily driven by reduced numbers of B cells and CD4+ T cells. However, Wildling mice had a higher proportion of class-switched germinal center B cells, plasma cells, and memory B cells, and significantly higher levels of serum antibodies than conventional laboratory mice. Wildling mice also exhibited significantly higher frequencies of CD44⁺CD62L⁺ central memory and CD44⁺CD62L⁻ effector memory T cells in spleen and lung compared to conventional laboratory mice. This immune status was associated with increased production of a broad range of cytokines in vivo and upon ex vivo stimulation of immune cells with PMA/ionomycin. We previously described that Wildling mice but not conventional laboratory mice predict the phase I clinical response of humans to the CD28 superagonist antibody TGN1412 (Science 2019, PMID: 31371577). This antibody was developed to expand regulatory T cells as a treatment of autoimmune diseases. While conventional laboratory mice responded to CD28 superagonist injection with an increase in Treg frequency, Wildling mice did not exhibit this response. Rather, they displayed increased cytokine levels, phenocopying the cytokine storm of humans. In FY’25, we identified the relative contribution of innate and adaptive immune cell populations to this enhanced cytokine response and reported that TNF-alpha and IFN-gamma-producing CD4+ and CD8+ T cells account for most of the response within 2 hours after CD28 superagonist injection. Importantly, this immunological phenotype remained stable over > 5 years in the Wildling mouse colony and was transferrable to conventional laboratory mice via either early life cross-fostering or adult-life co-housing. The transferability of the immune phenotype via co-housing increases the utility of the Wildling model for immunological research.