|Ivaylo Ivanov, Ph.D.
A vast and diverse community of microorganisms lives in a symbiotic relationship within the human body. These resident microorganisms, mostly composed of bacteria, are also known as the commensal microbiota. Commensal bacteria are indispensible for the proper metabolic and immune functions of the host. It has recently become obvious that commensal bacteria are important modulators of intestinal immune homeostasis and that the composition of the microbiota is a major determining factor of the type and robustness of mucosal immune responses.
Our laboratory is interested in identifying specific examples of immunomodulatory interactions between commensals and the host as well as the underlying mechanisms. In order to study the effects of individual members of the gut microbiota on immune homeostasis in vivo, we are studying germ-free animals colonized with defined bacterial species. Using this system, we recently showed that different components of the intestinal microbiota regulate the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg) in the small intestinal lamina propria. Th17 cells, which provide protection from extracellular pathogens at mucosal surfaces and are important mediators of pathogenicity in multiple models of autoimmune inflammation, were induced by certain components of the gut microbiota. We identified segmented filamentous bacteria (SFB) as one of these components. SFB-mediated induction of Th17 cells represents an example of a commensal species that specifically induces an effector T cell subset and skews mucosal immune responses. SFB are unique among the commensals in their ability to interact closely with intestinal epithelial cells.
One of the main directions in the lab will be the characterization of mechanisms by which SFB exert their immunomodulatory effects. In particular we are focusing on molecular mechanisms involved in SFB adhesion to intestinal epithelium and Th17 cell induction and the bacterial genes involved in this process. Another general direction in the lab is the characterization of immune subsets in the lamina propria, such as intestinal dendritic cell populations, innate lymphoid cells, and intestinal epithelial cells, that are involved in transmitting signals from commensal bacteria and generating the unique cytokine environment for Th17 and Treg differentiation; as well as the role of the induced immune responses in combating intestinal infections. We are utilizing a collection of knockout and reporter mouse lines to evaluate the roles of the individual subsets.
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Figure 1 (left) and Figure 2 (center).
Segmented filamentous bacteria (SFB) in the terminal ileum. Figure 3 (right).
Cluster of dendritic cells (green) and innate lymphoid cells (red) in a small intestinal villous crypt. Hover over any figure for an enlarged view.
- Panea, C., Farkas, A.M., Goto, Y., Abdollahi-Roodsaz, S., Lee, C., Koscso, B., Gowda, K., Hohl, T.M., Bogunovic, M. and Ivanov I.I. (2015) Intestinal monocyte-derived macrophages control commensal antigen-specific Th17 responses. Cell Reports 12: 1314-1324.
- Farkas, A.M. and Ivanov, I.I. (2015) Escaping negative selection: ILC you in the gut. Immunity 43: 12-14.
- Farkas, A.M., Panea, C., Goto, Y., Nakato, G., Galan-Diez, M., Narushima, S., Honda, K. and Ivanov, I.I. (2015) Induction of Th17 cells by segmented filamentous bacteria in the murine intestine. J. Immunol. Methods 421: 104-111.
- Goto, Y., Obata, T., Kunisawa, J., Sato, S., Ivanov, II, Lamichhane, A., Takeyama, N., Kamioka, M., Sakamoto, M., Matsuki, T., Setoyama, H., Imaoka, A., Uematsu, S., Akira, S., Domino, S.E., Kulig, P., Becher, B., Renauld, J.C., Sasakawa, C., Umesaki, Y., Benno, Y. and Kiyono, H. (2014) Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345: 1254009.
- Goto, Y., Panea, C., Nakato, G., Cebula, A., Lee, C., Diez, M.G., Laufer, T.M., Ignatowicz, L. and Ivanov, I.I. (2014) Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40: 1-14.
- Goto, Y. and Ivanov, I.I. (2013) Intestinal epithelial cells as mediators of the commensal-host immune crosstalk. Immunol. Cell Biol. 91: 204-214.
- Ivanov, I.I. and Honda, K. (2012) Intestinal commensal microbes as immune modulators. Cell Host Microbe 12: 496-508.
- Sczesnak, A., Segata, N., Qin, X., Gevers, D., Petrosino, J.F., Huttenhower, C., Littman, D.R. and Ivanov, I.I. (2011) The genome of Th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10: 1-13.
- Ivanov, I.I. and Littman D.R. (2011) Modulation of immune homeostasis by commensal bacteria. Current Opinions in Microbiology 14: 106-114.
- Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., Taniguchi, T., Takeda, K., Hori, S., Ivanov, I.I., Umesaki, Y., Itoh, K. and Honda, K. (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337-341.
- Ivanov, I.I. and Littman DR. (2010) Segmented filamentous bacteria take the stage. Mucosal Immunology 3: 209-112.
- Wu, H.J., Ivanov, I.I., Darce, J., Hattori, K., Shima, T., Umesaki, Y., Littman, D.R., Benoist, C. and Mathis, D. (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32: 815-827.
- Bounocore, S., Ahern, P.P., Uhlig, H.H., Ivanov, I.I., Littman, D.R., Maloy, K.J. and Powrie, F. (2010) Innate lymphoid cells drive IL-23 dependent innate intestinal pathology. Nature 464: 1371-5.
- Ivanov, I.I., Atarashi, K., Manel, N., Brodie, E.L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K.C., Santee, C.A., Lynch, S.V., Tanoue, T., Imaoka, A., Itoh, K., Takeda, K., Umesaki, Y., Honda, K. and Littman, D.R. (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139: 1-14.
- Luci, C.*, Reynders, A.*, Ivanov, I.I.*, Cognet, C., Chasson, L., Hardwigsen, J., Anguiano, E., Banchereau, J., Chaussabel, D., Dalod, M., Littman, D.R., Vivier, E. and Tomasello, E. (2009) Differential roles of the transcription factor RORgt in the development of NKp46+ lymphoid-tissue inducer-like cells and NKp46+ natural killer cells in gut and skin. Nature Immunology 10: 75-82. (*co-first authors)
- Takatori, H., Kanno, Y., Watford, W.T., Tato, C.M., Weiss, G., Ivanov, I.I., Littman, D.R. and O'Shea, J.J. (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. The Journal of Experimental Medicine 206: 35-41.
- Lepkes, M., Becker, C., Ivanov, I.I., Hirth, S., Wirtz, S., Neufert, C., Pouly, S., Murphy, A.J., Valenzuela, D.M., Yancopoulos, G.D., Becher, B., Littman, D.R. and Neurath, M.F. (2009) RORgamma expressing Th17 cells drive chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136: 257-67.
- Ivanov, I.I., Frutos, R.L., Manel, N., Yoshinaga, K., Rifkin, D.B., Sartor, R.B., Finlay, B.B. and Littman, D.R. (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host and Microbe 4: 337-49.
- Tsuji, M., Suzuki, K., Kitamura, H., Maruya, M., Kinoshita, K., Ivanov, I.I., Itoh, K., Littman, D.R. and Fagarasan, S. (2008) Requirement for adult RORgt+LTi cells in formation of isolated lymphoid follicles and T-independent generation of IgA in the gut. Immunity 29: 261-71.
- Zhou, L., Lopes, J., Chong, M.M.W., Ivanov, I.I., Min, R., Victora, G.D., Du, J., Rubtsov, Y.P., Rudensky, A., Ziegler, S.F. and Littman, D.R. (2008) TGF-b-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgt function. Nature 453: 236-40.
- Zhou, L., Ivanov, I.I., Spolski, R., Min, R., Shenderov, K., Egawa, T., Levy, D.E., Leonard, W.J. and Littman, D.R. (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunology 8: 967-74.
- Nguyen, H.H., Zemlin, M., Ivanov, I.I., Andrasi, J., Zemlin, C., Vu, H.L., Schelonka, R., Schroeder, H.W. Jr. and Mestecky, J. (2007) Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire. The Journal of Virology 81: 9331-8.
- Ivanov, I.I., McKenzie, B.S., Zhou, L., Tadokoro, C., Lepelley, A., Lafaille, J.J., Cua, D.J., and Littman, D.R. (2006) The orphan nuclear receptor RORgt directs the differentiation program of pro-inflammatory IL-17+ T helper cells. Cell 126: 1121-33.
- Ippolito, G.C., Schelonka, R.L., Zemlin, M., Ivanov, I.I., Kobayashi, R., Zemlin, C., Gartland, G.L., Nitschke, L., Pelkonen, J., Fujihashi, K., Rajewsky, K. and Schroeder, H.W., Jr. (2006) Forced usage of positively charged amino acids in immunoglobulin CDR-H3 impairs B cell development and antibody production. The Journal of Experimental Medicine 203: 1567-78.
- Schelonka, R.L.*, Ivanov, I.I.*, Jung, D.H., Ippolito, G.C., Nitschke, L., Zhuang, Y., Gartland, G.L., Pelkonen, J., Alt, F.W., Rajewsky, K. and Schroeder, H.W., Jr. (2005) A Single DH Gene Segment Creates Its Own Unique CDR-H3 Repertoire And Is Sufficient For B Cell Development And Immune Function. The Journal of Immunology 175: 6624-32. (*co-first authors)
- Ivanov, I.I., Schelonka, R.L., Zhuang, Y., Gartland, G.L., Zemlin, M., and Schroeder, H.W., Jr. (2005) Development of the expressed Ig CDR-H3 repertoire is marked by focusing of constraints in length, amino acid use, and charge, that are first established in early B cell progenitors. The Journal of Immunology 174: 7773-7780.
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