The focus and long-term research goals of the Sonnenberg Laboratory are to interrogate the mechanisms that maintain a state of health in the human gastrointestinal tract. This is a considerable challenge given the enormous surface area of this organ in which a single layer of intestinal epithelial cells segregates an estimated 100 trillion commensal bacteria from a significant portion of our bodies total immune system. While interactions between mammalian hosts and commensal bacteria are normally beneficial, it is becoming increasingly clear the dysregulated interactions can result in chronic inflammation. Further, emerging studies in patient populations indicate that abnormal host immune responses to commensal bacteria are causally-linked to the pathogenesis and progression of numerous chronic infectious, inflammatory and metabolic diseases, including inflammatory bowel disease (IBD), HIV/AIDS, viral hepatitis, cardiovascular disease, obesity, diabetes and cancer. Ongoing research in the Sonnenberg Laboratory aims to (1) interrogate the pathways that regulate normally beneficial host interactions with commensal bacteria, (2) determine how these pathways become disrupted in chronic human diseases, and (3) identify novel therapeutic targets to prevent or limit dysregulated host-commensal bacteria relationships in human disease.
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.
The Sonnenberg Lab has focused extensively on interrogating the role of group 3 RORγt+ ILCs in regulating interactions between intestinal commensal bacteria and the mammalian immune system. In our recent and ongoing research, we have identified populations of group 3 RORγt+ ILCs in the intestinal tissues of healthy humans, non-human primates and mice that play critical roles in regulating host-commensal bacteria relationships via two distinct mechanisms. First, through production of IL-22, ILCs were found to regulate systemic immune cell homeostasis by promoting the anatomical containment of a subset of commensal bacteria that normally resides in the gut-associated lymphoid-tissues of healthy humans, non-human primates and mice. Second, through expression of MHCII, ILCs were found to regulate CD4+ T cell responses to intestinal commensal bacteria and prevent chronic intestinal inflammation. This regulation occurred through a selection process in the intestine that resulted in a deletion of pro-inflammatory commensal bacteria-specific T cells, similar to what occurs for self-specific T cells in the thymus. Ongoing research in the Sonnenberg Lab is focused on interrogating functional interactions between ILCs, the adaptive immune system and lymphoid tissue-resident commensal bacteria, and their involvement in health and disease.
We have also recently launched a pioneering translational research effort involving clinical collaborators at Weill Cornell Medical College, The Children’s Hospital of Philadelphia and other research institutions to examine primary human samples from both healthy individuals and defined patient populations. Our ongoing research will further interrogate ILC responses and interactions with commensal bacteria 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 that may aid in the development of novel therapeutics to prevent or treat chronic human diseases.
Talented graduate students and postdoctoral researchers are encouraged to directly contact Dr. Sonnenberg to discuss potential rotation projects and open positions in the laboratory.
Fung T.C., Bessman N.J., Hepworth M.R., Kumar N., Shibata N., Kobuley D., Wang K., Ziegler C.G.K., Goc J., Shima T., Umesaki Y., Sartor R.B., Sullivan K.V., Lawley T.D., Kunisawa J., Kiyono H., Sonnenberg G.F. (2016) Lymphoid tissue-resident commensal bacteria promote members of the IL-10 cytokine family to establish mutualism. Immunity [PMCID: in progress].
Withers D.R., Hepworth M.R., Wang X., Mackley E.C., Halford E.E., Dutton E.E., Marriott C.L., Brucklacher-Waldert V., Veldhoen M., Kelsen J., Baldassano R.N., Sonnenberg G.F. (2016) Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nature Medicine [PMCID: in progress].
Hepworth M.R., Fung T.C., Masur S.H., Kelsen J.R., McConnell F.M., Dubrot J., Withers D.R., Hugues S., Farrar M.A., Reith W., Eberl G., Baldassano R.N., Laufer T.M., Elson C.O., Sonnenberg G.F. (2015) Group 3 Innate lymphoid cells mediated intestinal selection of commensal bacteria-specific CD4+ T cells. Science [PMCID: in progress].
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 [PMCID: in progress].
Kelsen J.R., Dawany N., Moran C.J., Petersen B.S., Sarmady M., Sasson A., Pauly-Hubbard H., Martinez A., Maurer K., Soong J., Rappaport E., Franke A., Keller A., Winter H.S., Mamula P., Piccoli D., Artis D., Sonnenberg G.F., Daly M., Sullivan K.E., Baldassano R.N., Devoto M. (2015) Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease. Gastroenterology [PMCID: in progress].
Sonnenberg G.F., Artis D. (2015) Innate lymphoid cells in the initiation, regulation and resolution of inflammation Nature Medicine [PMCID: in progress].
Wagage S., Harms Pritchard G., Dawson L., Buza E.L., Sonnenberg G.F., Hunter C.A. (2015) The group 3 innate lymphoid cell defect in aryl hydrocarbon receptor deficient mice is associated with T cell hyperactivation during intestinal infection. PLoS One [PMCID:PMC4444139].
Kelsen J.R., Baldassano R.N., Artis D., Sonnenberg G.F. (2015) Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cellular and Molecular Gastroenterology and Hepatology [PMCID: in progress].
Mackley E.C., Houston S., Marriott C.L., Halford E.E., Lucas B., Carovic V., Filbey K.J., Maizels R.M., Hepworth M.R., Sonnenberg G.F., Miling S., Withers D.R. (2015) CCR7-dependent trafficking or RORg (+) ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nature Communication. [PMC4354100].
Hepworth M.R., Sonnenberg G.F. (2014) Regulation of the adaptive immune system by innate lymphoid cells. Current Opinion in Immunology. Mar 1;27C:75-82 [PMC3979357].
Sonnenberg G.F. (2014). Regulation of intestinal health and disease by innate lymphoid cells. International Immunology. May 12. pii: dxu052 [PMC4142604].
Fung, T.C., Artis, D., Sonnenberg G.F. (2014) Anatomical localization of commensal bacteria in immune cell homeostasis and disease. Immunological Reviews. Jul;260(1):45-49 [PMC4216679].
Hepworth M.R., Monticelli L.A., Fung T.C., Ziegler C.G.K., Grunberg S., Sinha R., Mantegazza A.R., Ma H.L., Crawford A., Angelosanto J.M., Wherry E.J., Koni P.A., Bushman F.D., Elson C.O., Eberl G., Artis D., Sonnenberg G.F. (2013) Innate lymphoid cells regulate CD4+ T cell responses to intestinal commensal bacteria. Nature [PMC3699860].
Sonnenberg G.F., Mjosberg J., Spits H., Artis D. (2013) Snapshot: Innate lymphoid cells. Immunity [PMID24012419]
Sonnenberg G.F. and Artis D. (2012) Innate lymphoid cell interactions with the microbiota: implications for intestinal health and disease. Immunity. [PMC3495160].
Sonnenberg G.F., Monticelli L.A., Alenghat T., Fung T.C., Hutnick N.A., Kunisawa J., Shibata N., Grunberg S., Sinha R., Zahm A.M., Tardif M.R., Sathaliyawala T., Kubota M., Farber D.L., Collman R.G., Shaked A., Fouser L.A., Weiner D.B., Tessier P.A., Friedman J.R., Kiyono H., Bushman F.D., Chang K.M., Artis D. (2012) Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science [PMC3659421].
Monticelli L.A., Sonnenberg G.F., Abt M.C., Alenghat T., Ziegler C.G.K., Doering T.A., Angelosanto J.M., Laidlaw B.J., Yang C.Y., Sathaliyawala T., Kubota M., Tuner D., Diamond J.M., Goldrath A.W., Farber D.L., Collman R.G., Wherry E.J., Artis D. (2011) Innate lymphoid cells promote lung tissue homeostasis following acute influenza virus infection. Nature Immunology [PMC3320042].
Sonnenberg G.F., Fouser L.A., Artis, D. (2011) Border Patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nature Immunology. [PMID: 21502992].
Sonnenberg G.F., Monticelli L.A., Elloso M.M., Fouser L.A., Artis D. (2011) CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34:122-134. [PMC3035987].
Sonnenberg G.F., Nair M.G., Kirn T.J., Zaph C., Fouser L.A., Artis D. (2010) Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. Journal of Experimental Medicine [PMC2882840].