Sequential innate and adaptive immunity establishes non-inflammatory gut commensalism and physiologic host lipid metabolism

Authors

• K Mao
• AP Baptista
• S Tamoutounour
• L Zhuang
• N Bouladoux
• AJ Martins
• Y Huang
• MY Gerner
• Y Belkaid
• RN Germain

Abstract

The mammalian gut is colonized by numerous microorganisms termed the microbiota, which have a mutually beneficial relationship with their host. In normal individuals, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation. Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens, but how these two major lymphoid cell populations each contribute to shaping the mature commensal microbiome and help maintain tissue homeostasis has not been determined. Using advanced multiplex quantitative imaging methods, here we show an extensive and persistent pSTAT3 signature in ILC3s and intestinal epithelial cells (IECs) induced by IL-23 and IL-22 in animals lacking CD4+ T cells. In contrast, in immune-competent mice, there is only transient pSTAT3 activation induced by microbial colonization at weaning. This early signature is extinguished by Treg and Th17 cells as CD4+ T cell immunity develops in response to the expanding commensal burden. Our data show that innate and adaptive lymphocytes adopt different strategies to establish the commensal state and have different effects on microbiota, with the activity of adaptive lymphocytes dominating over that of the innate lymphoid cells in this circumstance. Physiologically, the persistent IL-22 production from ILC3s that occurs in the absence of adaptive CD4+ T cell activities results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady state commensalism and tissue metabolic homeostasis.

Scientific Focus Area: Immunology

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