Modeling Dirty Timestamp Mice to Assess the Impact of Perinatal Exposure to Diverse Pathogenic Microbes on the Functional Programming of Group 1 ILCs

Early-life microbial exposure is a key determinant of immune system development, influencing both innate and adaptive immune responses in ways that persist throughout life. During the perinatal period, neonates transition from the sterile environment of the uterus to a microbial-rich external world, where interactions with commensal, symbiotic, and pathogenic microbes provide essential signals for immune education. Epidemiological studies reveal that infants raised in microbially diverse environments—such as farms or households with pets—exhibit reduced susceptibility to allergic diseases and autoimmune disorders, underscoring the role of early microbial encounters in immune tolerance and resilience. In contrast, modern lifestyles characterized by reduced microbial exposure, excessive sanitation, and increased antibiotic use have been implicated in the rising incidence of immune dysregulation, including asthma, inflammatory bowel disease, and atopic conditions. These findings highlight the necessity of understanding how perinatal microbial diversity influences immune cell ontogeny at a mechanistic level. While previous studies have largely focused on the impact of microbial exposure on adaptive immunity, the extent to which early microbial exposure shapes the development and functional specification of innate lymphocytes remains poorly understood. Natural killer (NK) cells, as critical effectors of innate immunity, exhibit remarkable developmental plasticity and are poised to respond rapidly to infection, malignancy, and inflammatory stimuli. However, how perinatal microbial exposure influences NK cell fate commitment remains a fundamental gap. Our preliminary results in specific pathogen-free (SPF) mice—where microbial exposure is restricted—indicate that NK cell cytotoxicity is progressively acquired over time, exhibiting an inverse relationship to TGFβ signaling. Notably, NK cells share developmental pathways with other Group 1 innate lymphoid cells (ILC1s), a population that remains tissue-resident and exhibits distinct functional attributes. The balance between NK cells and ILC1s is tightly regulated in adult tissues, but whether microbial exposure during the perinatal period influences this equilibrium remains unclear. By utilizing 'dirty' mice to model diverse microbial environments, we will: determine impact of perinatal microbial exposure on NK cell fate specification (Aim 1), determine the impact of perinatal microbial exposure on the timing of NK cell cytotoxicity acquisition (Aim 2), and determine the impact of perinatal microbial exposure on NK-to-ILC1 equilibrium (Aim 3). Our research will provide crucial insights into how early-life TGFβ and perinatal microbial diversity—two pivotal yet opposing influences—interact to shape NK cell ontogeny, offering a novel conceptual framework that could redefine preventive and therapeutic strategies in pediatric immunology. This previously undescribed axis of immune modulation promises to advance our understanding of immune resilience and susceptibility in early development, paving the way for targeted interventions that optimize immune health from infancy. Project Number: 1R21AI196799-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Yasmina Laouar | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $411,078 | Activity Code: R21 | Study Section: Immunity and Host Defense Study Section[IHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19679901