Description of Research Expertise

The mammalian gastrointestinal tract is colonized with trillions of beneficial commensal bacteria that are essential for normal development, physiology and health, and is also an extremely immunologically active site, containing up to 80% of the body’s total immune cells. In healthy individuals, a balance is maintained between the immune system and intestinal commensal bacteria that is beneficial for both. However, dysregulated interactions between the mammalian immune system and intestinal commensal bacteria can promote local and systemic inflammation, and have been causally linked with the pathogenesis and progression of numerous chronic infectious, inflammatory and metabolic diseases such as HIV, hepatitis, cancer, diabetes, cardiovascular disease and inflammatory bowel disease. The goals of the Sonnenberg lab are to utilize multidisciplinary immunologic and microbiologic approaches to delineate the complex pathways that regulate normal host-commensal bacteria relationships and prevent chronic inflammation in the context of human health and disease.

Recent research from the Sonnenberg and other laboratories has identified populations of intestinal-resident innate lymphoid cells (ILCs) that play critical roles in the regulation of immunity, inflammation, and tissue homeostasis. ILCs are an emerging family of immune cells that depend on the transcription factor Id2 for their development, differentiate from lymphoid progenitors and are independent of somatic recombination. ILCs share striking similarities to heterogeneous populations of effector CD4+ and CD8+ 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. Specifically, group 1 ILCs are T-bet+, activated by IL-18 and IL-12 and express IFNγ and TNFα. Group 1 ILCs include natural killer (NK) cells and other T-bet+ non-NK cell subsets, and promote anti-viral immunity and tumor regression. Group 2 ILCs are dependent on GATA3 and RORα for their development, can be activated by IL-25, IL-33 and TSLP and express IL-5, IL-9, IL-13 and amphiregulin. Group 2 ILCs include cells termed natural helper cells, nuocytes and innate helper type 2 cells, and have been found to promote allergic inflammation, tissue repair and immunity to helminth parasites. Group 3 ILCs are RORγt-dependent, are activated by IL-1β and IL-23 and express IL-22 and IL-17A. Group 3 ILCs include cell termed lymphoid-tissue inducer (LTi) cells and NK-22 cells, and have been found to promote intestinal inflammation, tissue repair and immunity to extracellular bacteria.

In our recent and ongoing research, we have identified populations of IL-22-producing group 3 RORγt+ ILCs in the intestinal tissues of healthy humans, non-human primates and mice. These populations of group 3 ILCs were found to be essential for promoting innate immunity to pathogenic enteric bacteria. Furthermore, in the steady state of healthy mice, RORγt+ ILCs were found to promote the anatomical containment of commensal bacteria and limit systemic inflammation. Specifically, in the absence of ILCs, Alcaligenes species, a group of commensal bacteria that normally resides in the gut-associated lymphoid-tissues of healthy humans, non-human primates and mice, disseminates to peripheral organs and causes chronic low-grade inflammation in mice. This provokes the hypothesis that interactions between mammals and commensal bacteria is a highly sophisticated process in which distinct modules of the innate and adaptive immune response regulate selective populations of commensal bacteria. Ongoing research in the Sonnenberg lab is focused on interrogating the mechanistic role of ILCs in regulating host interactions with intestinal commensal bacteria and their involvement in the pathogenesis of chronic diseases.

We have also recently launched a pioneering translational research effort involving clinical collaborators at Penn, The Children’s Hospital of Philadelphia, the Philadelphia VA Medical Center and other research institutions to examine primary human samples from both healthy individuals and defined patient populations. For example, we have recently identified an association between dysregulated immune responses to Alcaligenes bacteria and disease progression in patients suffering from inflammatory bowl disease or Hepatitis C infection. 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.

Graduate students and talented postdoctoral researchers are encouraged to contact Dr. Sonnenberg to discuss potential rotation projects and open positions in the laboratory.

*Recent publications

Sonnenberg G.F. and Artis D. (2012) Innate lymphoid cell interactions with the microbiota: implications for intestinal health and disease. Immunity 37: 601-610. [PMID: 23084357]

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 336: 1321-1325 [PMID: 22674331].

Monticelli L.A., Sonnenberg G.F., Artis D. (2012) Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung. Current Opinion in Immunology 24: 1-6 [PMID: 22521139].

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 12: 1045-54 [PMID: 21946417].

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 12: 383-390. [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. [PMID: 21194981].