Letter | Published:

Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism

Nature volume 554, pages 255259 (08 February 2018) | Download Citation


The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host1,2,3. Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation4,5. Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens6,7, but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4+ T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4+ T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4+ T-cell activity 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.

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  1. 1.

    & Microbiota-mediated inflammation and antimicrobial defense in the intestine. Annu. Rev. Immunol. 33, 227–256 (2015)

  2. 2.

    , & Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012)

  3. 3.

    & Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014)

  4. 4.

    , & The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2011)

  5. 5.

    , , & How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016)

  6. 6.

    & The biology of innate lymphoid cells. Nature 517, 293–301 (2015)

  7. 7.

    & Innate lymphoid cell function in the context of adaptive immunity. Nat. Immunol. 17, 783–789 (2016)

  8. 8.

    , , , & Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity 37, 364–376 (2012)

  9. 9.

    , & Strategically localized dendritic cells promote rapid T cell responses to lymph-borne particulate antigens. Immunity 42, 172–185 (2015)

  10. 10.

    et al. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature 528, 225–230 (2015)

  11. 11.

    , & STAT3-activating cytokines: a therapeutic opportunity for inflammatory bowel disease? J. Interferon Cytokine Res. 35, 340–350 (2015)

  12. 12.

    et al. A T-bet gradient controls the fate and function of CCR6RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013)

  13. 13.

    et al. Induction of intestinal TH17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009)

  14. 14.

    et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector TH17 responses. Cell 163, 381–393 (2015)

  15. 15.

    et al. Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection. Immunity 40, 25–39 (2014)

  16. 16.

    et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010)

  17. 17.

    et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925–938 (2013)

  18. 18.

    , & Timing, localization, and persistence of colonization by segmented filamentous bacteria in the neonatal mouse gut depend on immune status of mothers and pups. Infect. Immun. 69, 3611–3617 (2001)

  19. 19.

    et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal TH17 cell differentiation. Immunity 40, 594–607 (2014)

  20. 20.

    et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014)

  21. 21.

    , & The brave new world of innate lymphoid cells. Nat. Immunol. 16, 1–5 (2015)

  22. 22.

    & Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets. J. Exp. Med. 214, 1861–1876 (2017)

  23. 23.

    et al. Conventional CD4+ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol. 7, 1045–1057 (2014)

  24. 24.

    & TH17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010)

  25. 25.

    , , & A function for interleukin 2 in FOXP3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005)

  26. 26.

    et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014). 10.1038/nature13564

  27. 27.

    et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357, 912–916 (2017)

  28. 28.

    et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016)

  29. 29.

    et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017)

  30. 30.

    et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549, 282–286 (2017)

  31. 31.

    , , , & Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics. Science 352, 1533 (2016)

  32. 32.

    et al. Cultivating healthy growth and nutrition through the gut microbiota. Cell 161, 36–48 (2015)

  33. 33.

    et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013)

  34. 34.

    et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013)

  35. 35.

    , & featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014)

  36. 36.

    , & Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014)

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We thank Y. Choi and D.M. Kobuley for providing germ free Rag1−/− mice and performing SFB mono-colonization; M. Oukka and S. K. Durum for providing mice; M. Mack, B. Gao and Y. Umesaki for providing anti-CCR2 antibody, IL-22 adenovirus and SFB faecal pellets; C. Eigsti, V. Nair and J. Davis for cell sorting, scanning electron microscopy and microbiota analysis; J. Zhu for discussions; and members of the Laboratory of Systems Biology for their comments during the course of these studies and input during preparation of this manuscript. Y.H. was supported by an NIAID K99 award (1K99AI123350-01A1). This research was supported by the Intramural Research Program of NIAID, NIH.

Author information


  1. Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Kairui Mao
    • , Antonio P. Baptista
    •  & Ronald N. Germain
  2. Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Samira Tamoutounour
    • , Nicolas Bouladoux
    •  & Yasmine Belkaid
  3. Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Lenan Zhuang
  4. Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Andrew J. Martins
  5. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Yuefeng Huang
  6. Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98109, USA

    • Michael Y. Gerner


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K.M. designed and conducted most of the experiments and data analysis and prepared the manuscript; A.P.B., S.T. and Y.H. helped with cell isolation and transfer; L.Z. measured mouse body composition; N.B. performed the analysis of microbiota translocation; A.J.M. performed the RNA-seq and data analysis; M.Y.G. provided helpful suggestions regarding imaging and histo-cytometry; Y.B. provided helpful suggestions, discussed data interpretation and contributed to the manuscript; and R.N.G. designed experiments, interpreted data and helped to write the manuscript.

Competing interests

The authors declare no competing financial interests.

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Correspondence to Kairui Mao or Ronald N. Germain.

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