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Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ

Abstract

Major histocompatibility complex class II (MHCII) is dynamically expressed on intestinal epithelial cells (IECs) throughout the intestine, but its regulation remains poorly understood. We observed that spontaneous upregulation of IEC MHCII in locally bred Rag1−/− mice correlated with serum Interleukin (IL)-18, was transferrable via co-housing to commercially bred immunodeficient mice and could be inhibited by both IL-12 and IL-18 blockade. Overproduction of intestinal IL-18 due to an activating Nlrc4 mutation upregulated IEC MHCII via classical inflammasome machinery independently of immunodeficiency or dysbiosis. Immunodeficient dysbiosis increased Il-18 transcription, which synergized with NLRC4 inflammasome activity to drive elevations in serum IL-18. This IL-18-MHCII axis was confirmed in several other models of intestinal and systemic inflammation. Elevated IL-18 reliably preceded MHCII upregulation, suggesting an indirect effect on IECs, and mice with IL-18 overproduction showed activation or expansion of type 1 lymphocytes. Interferon gamma (IFNg) was uniquely able to upregulate IEC MHCII in enteroid cultures and was required for MHCII upregulation in several in vivo systems. Thus, we have linked intestinal dysbiosis, systemic inflammation, and inflammasome activity to IEC MHCII upregulation via an intestinal IL-18-IFNg axis. Understanding this process may be crucial for determining the contribution of IEC MHCII to intestinal homeostasis, host defense, and tolerance.

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Fig. 1: Rag1-immunodeficiency is associated with a microbiota-dependent increase in intestinal epithelial cell MHCII.
Fig. 2: Elevated MHCII in Rag1−/− mice is driven by a transferable microbial dysbiosis.
Fig. 3: Colonic IEC MHCII correlates with serum IL-18 in Rag1−/− mice and can be blunted by IL-18 and IL-12 blockade.
Fig. 4: NLRC4 inflammasome hyperactivity, IL-18bp deficiency, and transgenic IL-18 expression increase SI MHCII expression.
Fig. 5: Classical inflammasome components are required and synergize with immunodeficiency to modulate Nlrc4-inflammasome induced elevations of serum IL-18 and IEC MHCII.
Fig. 6: Tritrichomonas colonization and systemic TLR9 activation induce IL-18 dependent upregulation of colonic and SI IEC MHCII.
Fig. 7: Diverse in vivo triggers of MHCII expression all require IFNg.
Fig. 8: Elevated IL-18 alters lamina propria immune cell composition in Rag1−/− and NLRC4TS/TS mice.

References

  1. 1.

    Koyama, M. et al. MHC class II antigen presentation by the intestinal epithelium initiates graft-versus-host disease and is influenced by the microbiota. Immunity 51, 885–898 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Wosen, J. E., Mukhopadhyay, D., Macaubas, C. & Mellins, E. D. Epithelial MHC class II expression and its role in antigen presentation in the gastrointestinal and respiratory tracts. Front Immunol. 9, 2144 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Hershberg, R. M. et al. Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. J. Clin. Investig. 100, 204–215 (1997).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Jamwal, D. R. et al. Intestinal epithelial expression of MHCII determines severity of chemical, T cell-induced, and infectious colitis in mice. Gastroenterology 159, 1342–1356.e1346 (2020).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Thelemann, C. et al. Interferon-gamma induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis. PLoS One 9, e86844 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Bekiaris, V., Persson, E. K. & Agace, W. W. Intestinal dendritic cells in the regulation of mucosal immunity. Immunol. Rev. 260, 86–101 (2014).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Grainger, J. R., Askenase, M. H., Guimont-Desrochers, F., da Fonseca, D. M. & Belkaid, Y. Contextual functions of antigen-presenting cells in the gastrointestinal tract. Immunol. Rev. 259, 75–87 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Goto, Y. et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40, 594–607 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Maggio-Price, L. et al. Lineage targeted MHC-II transgenic mice demonstrate the role of dendritic cells in bacterial-driven colitis. Inflamm. Bowel Dis. 19, 174–184 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Hepworth, M. R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320 (2018). e1322.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Ting, J. P. & Trowsdale, J. Genetic control of MHC class II expression. Cell 109, S21–S33 (2002). Suppl.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Umesaki, Y., Okada, Y., Matsumoto, S., Imaoka, A. & Setoyama, H. Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class II molecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse. Microbiol Immunol. 39, 555–562 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Bunker, J. J. & Bendelac, A. IgA responses to microbiota. Immunity 49, 211–224 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Weiss, E. S. et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood 131, 1442–1455 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Poznanski, S. M. et al. Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells. J. Innate Immun. 9, 511–525 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Hoshino, T. et al. Cutting edge: IL-18-transgenic mice: in vivo evidence of a broad role for IL-18 in modulating immune function. J. Immunol. 166, 7014–7018 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Girard-Guyonvarc’h, C. et al. Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood 131, 1430–1441 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  20. 20.

    Chae, J. J. et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity 34, 755–768 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Vance, R. E. The NAIP/NLRC4 inflammasomes. Curr. Opin. Immunol. 32, 84–89 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Rauch, I. et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity 46, 649–659 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Van Opdenbosch, N. & Lamkanfi, M. Caspases in cell death, inflammation, and disease. Immunity 50, 1352–1364 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Canna, S. W. et al. Interferon-gamma mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice. Arthritis Rheum. 65, 1764–1775 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Behrens, E. M. et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J. Clin. Investig. 121, 2264–2277 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Tsoukas, P. et al. Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation. Blood 136, 2162–2174 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Chudnovskiy, A. et al. Host-protozoan interactions protect from mucosal infections through activation of the inflammasome. Cell 167, 444–456.e414 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Escalante, N. K. et al. The common mouse protozoa Tritrichomonas muris alters mucosal T cell homeostasis and colitis susceptibility. J. Exp. Med 213, 2841–2850 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Schneider, C. et al. A metabolite-triggered tuft. Cell-ILC2 Circuit Drives Small Intestinal Remodeling. Cell 174, 271–284.e214 (2018).

    CAS  PubMed  Google Scholar 

  31. 31.

    Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Al Nabhani, Z. et al. A weaning reaction to microbiota is required for resistance to immunopathologies in the adult. Immunity 50, 1276–1288.e1275 (2019).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Skoskiewicz, M. J., Colvin, R. B., Schneeberger, E. E. & Russell, P. S. Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon. J. Exp. Med 162, 1645–1664 (1985).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Stagg, A. J. Intestinal dendritic cells in health and gut inflammation. Front Immunol. 9, 2883 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Ratsimandresy, R. A., Indramohan, M., Dorfleutner, A. & Stehlik, C. The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway. Cell Mol. Immunol. 14, 127–142 (2017).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Bowcutt, R. et al. Heterogeneity across the murine small and large intestine. World J. Gastroenterol. 20, 15216–15232 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Olivares-Villagomez, D. & Kaer, V. L. Intestinal intraepithelial lymphocytes: sentinels of the mucosal barrier. Trends Immunol. 39, 264–275 (2018).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Stras, S. F. et al. Maturation of the HUman Intestinal Immune System Occurs Early in Fetal Development. Dev. Cell 51, 357–373.e355 (2019).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Torow, N., Marsland, B. J., Hornef, M. W. & Gollwitzer, E. S. Neonatal mucosal immunology. Mucosal Immunol. 10, 5–17 (2017).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Wosen, J. E. et al. Human intestinal enteroids model MHC-II in the gut epithelium. Front Immunol. 10, 1970 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Pai, R. K., Askew, D., Boom, W. H. & Harding, C. V. Regulation of class II MHC expression in APCs: roles of types I, III, and IV class II transactivator. J. Immunol. 169, 1326–1333 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Morris, A. C., Beresford, G. W., Mooney, M. R. & Boss, J. M. Kinetics of a gamma interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Mol. Cell Biol. 22, 4781–4791 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Hall, J. A. et al. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 34, 435–447 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Howitt, M. R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Drummond, C. G. et al. Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner. Proc. Natl Acad. Sci. USA 114, 1672–1677 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Miyoshi, H. & Stappenbeck, T. S. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat. Protoc. 8, 2471–2482 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Bolyen, E. et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat. Biotechnol. 37, 852–857 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Callahan, B. J. et al. DADA2: high-resolution sample inference from Illumina amplicon data. Nat. Methods 13, 581–583 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Katoh, K., Misawa, K., Kuma, K. & Miyata, T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res 30, 3059–3066 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Price, M. N., Dehal, P. S. & Arkin, A. P. FastTree 2-approximately maximum-likelihood trees for large alignments. PLoS One 5, e9490 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    McDonald, D. et al. An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea. ISME J. 6, 610–618 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Van Winkle, J. A., Constant, D. A., Li, L. & Nice, T. J. Selective interferon responses of intestinal epithelial cells minimize tumor necrosis factor alpha cytotoxicity. J Virol. 94, e00603–e00620 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

S.C., C.S., and V.D. were supported by NICHD R01HD098428. L.V.D.K. and A.H.P.B. were supported by autoimmunity and immunopathology T32 (5T32AI089443-11). T.H. was supported by the Kenneth Rainin Foundation and R01DK120697. We also thanks Drs. Daniel Kastner and Jae Jin Chae (NHGRI); Dario Vignali, Warren Shlomchik, and Sarah Gaffen (University of Pittsburgh); Tomoaki Hoshino (Kurume University); and Richard Flavell (Yale University) for sharing key reagents.

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S.C. and L.V.D.K. planned and analyzed the experiments, which were conducted by L.V.D.K., C.S., V.D., E.W., J.V., L.Y., and S.C. A.H.P.B. performed the 16S analysis and is supervised by T.H. The manuscript was written by L.V.D.K. and S.C. and all authors reviewed and approved the manuscript prior to submission.

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Correspondence to L. A. Van Der Kraak or S. W. Canna.

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Van Der Kraak, L.A., Schneider, C., Dang, V. et al. Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ. Mucosal Immunol (2021). https://doi.org/10.1038/s41385-021-00419-1

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