The focus and long-term research goals of the Sonnenberg Laboratory are to interrogate the mechanisms by which the mammalian immune system controls tissue homeostasis, immunity, inflammation and cancer at mucosal barrier surfaces of the body. This is a considerable challenge given the enormous surface area of these sites, such as the gastrointestinal tract, which is home to an estimated 10 trillion microbes (termed the microbiota) and a majority of our body’s total immune system. While interactions between mammalian hosts and microbiota are normally beneficial, these interactions must be tightly regulated to prevent chronic inflammation. Studies in patient populations indicate that abnormal host immune responses to microbiota are causally-linked to the pathogenesis and progression of numerous chronic disorders, including inflammatory bowel disease (IBD), HIV/AIDS, viral hepatitis, cardiovascular disease, multiple sclerosis, Alzheimer’s diseases, autism, obesity, diabetes and cancer. Further, these interactions can influence the success or failure of multiple clinical therapies. Ongoing research in the Sonnenberg Laboratory aims to (1) interrogate the pathways that regulate normally beneficial host interactions with microbiota; (2) determine how these pathways become disrupted in multiple chronic human diseases; and (3) identify novel preventative, therapeutic or curative approaches to target the immune system and/or microbiota to benefit human health.
To better understand host-commensal bacteria interactions we have been studying the recently identified populations of intestinal-resident innate lymphoid cells (ILCs). ILCs are an emerging family of immune cells that differentiate, independent of somatic recombination, from IL-7Rα+ Id2-dependent lymphoid progenitors. ILCs share striking similarities to heterogeneous populations of effector T cells. As such, ILCs can currently be broadly classified into 3 groups based on their developmental requirements for specific transcription factors, common activating receptors and expression of effector cytokines. Group 1 ILCs are T-bet+, activated by IL-18 and IL-12, and express IFNγ. Group 2 ILCs are GATA-3-hi, activated by IL-25, IL-33 and TSLP, and express IL-4, IL-5, IL-9, IL-13 and amphiregulin. Group 3 ILCs are RORγt-dependent, activated by IL-1β and IL-23, and express IL-22 and IL-17. Importantly, group 3 ILCs have been found to be critical regulators of cytokine-mediated intestinal epithelial cell responses that promote immunity to extracellular bacteria, inflammation and tissue repair in the intestine.
We have also recently launched a pioneering translational research effort involving clinical collaborators at Weill Cornell Medicine and other research institutions to examine primary human samples from both healthy individuals and defined patient populations. Our ongoing research will further interrogate mucosal immune responses and interactions with microbiota in healthy and diseased primary human tissue samples. We anticipate that these studies will allow us to directly translate our findings in mouse models to clinically relevant information.
Talented graduate students and postdoctoral researchers are encouraged to directly contact Dr. Sonnenberg to discuss potential rotation projects and open positions in the laboratory.
Zhou L, Zhou W, Joseph AM, Chu C, Putzel GG, Fang B, Teng F, Lyu M, Yano H, Andreasson KI, Mekada E, Eberl G, Sonnenberg GF. Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nature Immunology. 2022 Jan 31. doi: 10.1038/s41590-021-01110-0. PMID: 35102343.
Grigg JB, Shanmugavadiv A, Regen T, Parkhurt CN, Ahmed A, Joseph AM, Mazzucco M, Gronke K, Diegenbach A, Eberl G, Vartanian T, Waisman A, Sonnenberg GF. Antigen presenting innate lymphoid cells orchestrate neuroinflammation. Nature. 2021 Dec;600(7890):707-712. doi: 10.1038/s41586-021-04136-4. Epub 2021 Dec 1. PMID: 34853467; PMCID: PMC8702489.
Teng F, Tachó-Piñot R, Sung B, Farber DL, Worgall S, Hammad H, Lambrecht BN, Hepworth MR, Sonnenberg GF. ILC3s control airway inflammation by limiting T cell responses to allergens and microbes. Cell Reports 2021 Nov 23;37(8):110051. doi: 10.1016/j.celrep.2021.110051. PMID: 34818549.
Goc J, Lv M, Bessman NJ, Flamar A, Sahota S, Suzuki H, Teng F, Putzel GG, JRI Live Cell Bank, Eberl G, Withers DR, Arthur JC, Shah MA, Sonnenberg GF. Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer. Cell. 2021. Sep 16;184(19):5015-5030.e16. doi: 10.1016/j.cell.2021.07.029. PubMed PMID: 34407392
Teng F, Goc J, Zhou L, Chu C, Shah MA, Eberl G, Sonnenberg GF. A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut. Science Immunology. 2019 Oct 4;4(40). pii: eaax1215. doi: 10.1126/sciimmunol.aax1215. PubMed PMID: 31586011.
Sonnenberg GF, Hepworth MR. Functional interactions between innate lymphoid cells and adaptive immunity. Nature Reviews Immunology. 2019 Jul 26. doi: 10.1038/s41577-019-0194-8. Review.PubMed PMID: 31350531.
Zhou L, Chu C, Teng F, Bessman NJ, Goc J, Santosa EK, Putzel GG, Kabata H, Kelsen JR, Baldassano RN, Shah MA, Sockolow RE, Vivier E, Eberl G, Smith KA, Sonnenberg GF. Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2. Nature. 2019 Apr;568(7752):405-409. doi: 10.1038/s41586-019-1082-x. Epub 2019 Apr 3. PubMed PMID: 30944470; PubMed Central PMCID: PMC6481643.
Joseph AM, Monticelli LA, Sonnenberg GF. Metabolic regulation of innate and adaptive lymphocyte effector responses. Immunological Reviews. 2018 Nov;286(1):137-147. doi: 10.1111/imr.12703. Review. PubMed PMID: 30294971; PubMed Central PMCID: PMC6195227.
Zhou L, Sonnenberg GF. Essential immunologic orchestrators of intestinal homeostasis. Science Immunology. 2018 Feb 9;3(20). pii: eaao1605. doi: 10.1126/sciimmunol.aao1605. Review. PubMed PMID: 29440266; PubMed Central PMCID: PMC6352895.
Grigg JB, Sonnenberg GF. Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases. Journal of Immunology. 2017 Jan 15;198(2):564-571. doi: 10.4049/jimmunol.1601621. Review. PubMed PMID: 28069751; PubMed Central PMCID: PMC5228396.
Fung TC, Bessman NJ, Hepworth MR, Kumar N, Shibata N, Kobuley D, Wang K, Ziegler CGK, Goc J, Shima T, Umesaki Y, Sartor RB, Sullivan KV, Lawley TD, Kunisawa J, Kiyono H, Sonnenberg GF. Lymphoid-Tissue-Resident Commensal Bacteria Promote Members of the IL-10 Cytokine Family to Establish Mutualism. Immunity. 2016 Mar 15;44(3):634-646. doi: 10.1016/j.immuni.2016.02.019. PubMed PMID: 26982365; PubMed Central PMCID: PMC4845739.
Withers DR, Hepworth MR, Wang X, Mackley EC, Halford EE, Dutton EE, Marriott CL, Brucklacher-Waldert V, Veldhoen M, Kelsen J, Baldassano RN, Sonnenberg GF. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nature Medicine. 2016 Mar;22(3):319-23. doi: 10.1038/nm.4046. Epub 2016 Feb 15. PubMed PMID: 26878233; PubMed Central PMCID: PMC4948756.
Goc J., Hepworth M.R., Sonnenberg G.F., (2015) Group 3 innate lymphoid cells: regulating host-commensal bacteria interactions in inflammation and cancer. International Immunology. 2016 Jan;28(1):43-52. doi: 10.1093/intimm/dxv056. Epub 2015 Oct 7. Review. PubMed PMID: 26451009; PubMed Central PMCID: PMC5891988.
Kelsen JR, Baldassano RN, Artis D, Sonnenberg GF. Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cellular Molecular Gastroenterology Hepatology. 2015 Sep 1;1(5):462-476. PubMed PMID: 26393237; PubMed Central PMCID: PMC4574301.
Sonnenberg G.F., Artis D. (2015) Innate lymphoid cells in the initiation, regulation and resolution of inflammation Nature Medicine. 2015 Jul;21(7):698-708. doi: 10.1038/nm.3892. Epub 2015 Jun 29. Review. PubMed PMID: 26121198; PubMed Central PMCID: PMC4869856.
Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM, Dubrot J, Withers DR, Hugues S, Farrar MA, Reith W, Eberl G, Baldassano RN, Laufer TM, Elson CO, Sonnenberg GF. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4⁺ T cells. Science. 2015 May 29;348(6238):1031-5. doi: 10.1126/science.aaa4812. Epub 2015 Apr 23. PubMed PMID: 25908663; PubMed Central PMCID: PMC4449822.
Fung TC, Artis D, Sonnenberg GF. Anatomical localization of commensal bacteria in immune cell homeostasis and disease. Immunological Reviews. 2014 Jul;260(1):35-49. doi: 10.1111/imr.12186. Review. PubMed PMID: 24942680; PubMed Central PMCID: PMC4216679.
Sonnenberg GF. Regulation of intestinal health and disease by innate lymphoid cells. International Immunology. 2014 Sep;26(9):501-7. doi: 10.1093/intimm/dxu052. Epub 2014 May 12. PubMed PMID: 24821261; PubMed Central PMCID: PMC4142604.
Hepworth MR, Sonnenberg GF. Regulation of the adaptive immune system by innate lymphoid cells. Current Opinions in Immunology. 2014 Apr;27:75-82. doi: 10.1016/j.coi.2014.01.013. Epub 2014 Mar 3. Review. PubMed PMID: 24594491; PubMed Central PMCID: PMC3979357.
Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, Mantegazza AR, Ma HL, Crawford A, Angelosanto JM, Wherry EJ, Koni PA, Bushman FD, Elson CO, Eberl G, Artis D, Sonnenberg GF. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013 Jun 6;498(7452):113-7. doi: 10.1038/nature12240. Epub 2013 May 22. PubMed PMID: 23698371; PubMed Central PMCID: PMC3699860.
Sonnenberg GF, Artis D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity. 2012 Oct 19;37(4):601-10. doi: 10.1016/j.immuni.2012.10.003. Review. PubMed PMID: 23084357; PubMed Central PMCID: PMC3495160.
Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, Shibata N, Grunberg S, Sinha R, Zahm AM, Tardif MR, Sathaliyawala T, Kubota M, Farber DL, Collman RG, Shaked A, Fouser LA, Weiner DB, Tessier PA, Friedman JR, Kiyono H, Bushman FD, Chang KM, Artis D. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. 2012 Jun 8;336(6086):1321-5. doi: 10.1126/science.1222551. Epub 2012 Jun 6. PubMed PMID: 22674331; PubMed Central PMCID: PMC3659421.