Ivaylo (Ivo) Ivanov Role of intestinal commensal microbiota in Th17 cell differentiation and function I am interested in how the composition of intestinal microbiota in the gut affects immune function. It has been known for some time that the presence of commensal bacteria in the intestine is required for a multitude of physiological functions. In addition, germ-free animals posess an under-developed immune system, both locally in the gut and systemically. Colonization of germ-free animals with commensals leads to "maturation" of the immune system, which includes, among other examples, development of organized gut-associated lymphoid tissues, recruitment of B and T cells to the lamina propria, and production of secretory IgA. However, it is currently unkown if and how different bacterial species stimulate different branches of the immune system in the gut. We have recently demonstrated that the composition of the gut bacterial microbiota is crucial in establishing the balance between Th17 cells and regulatory T cells (Tregs) in the lamina propria. We found that the ability to induce Th17 cells is a property not of all bacteria, but only of a small subset of intestinal microbes. I would like to address three main questions: 1) What are the Th17 cell inducing microbial species in the gut and 2) what are the microbiota-mediated signals for Th17 cell differentiation as well as 3) how are they transmitted from the gut lumen to the lamina propria. The goal of these studies is to identify bacterial species or products, which can be used to modulate the immune response to protect from infections with enteric pathogens or treat chronic inflammation. My PhD work at UAB addressed the fundamental question of generation of diversity (aka GOD) in the antibody repertoire. A comparative analysis of HCDR3 repertoires showed conserved pattern of amino acid utilization and hydropathicity in all species with adaptive immunity. Surprisingly, these characteristics were also constrained in a similar fashion in the germline sequence of the heavy chain locus and highly conserved in the genome throughout the vertebrate taxon. The germline sequence was dominant over selection mechanisms in defining the final HCDR3 repertoire as demonstrated by a gene-targeted model in which the coding sequence of the D-locus was modified. Publications 1. Ivanov II, Frutos RL, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host and Microbe 2008, 4(4):337-49 2. Luci C*, Reynders A*, Ivanov II*, Cognet C, Chasson L, Hardwigsen J, Anguiano E, Banchereau J, Chaussabel D, Dalod M, Littman DR, Vivier E, Tomasello E. 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 2008, accepted for publication 3. Lepkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, Pouly S, Murphy AJ, Valenzuela, DM, Yancopoulos GD, Becher B, Littman DR, Neurath MF. RORgamma expressing Th17 cells drive chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 2008, doi:10.1053/j.gastro.2008.10.018 4. Tsuji M, Suzuki K, Kitamura H, Maruya M, Kinoshita K, Ivanov II, Itoh K, Littman DR, and Fagarasan S. Requirement for adult RORgt+LTi cells in formation of isolated lymphoid follicles and T-independent generation of IgA in the gut. Immunity 2008, Aug; 29(2):261-71 5. Zhou L, Lopes J, Chong MMW, Ivanov II, Min R, Victora GD, Du J, Rubtsov YP, Rudensky A, Ziegler SF, and Littman DR. TGF-b-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORgt function. Nature 2008, 453(7192):236-40 6. Ivanov II, Zhou L, and Littman DR. Transcriptional regulation of Th17 cell differentiation. Seminars in Immunology 2007, Dec;19(6):409-17 7. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. 8. Nguyen HH, Zemlin M, Ivanov II, Andrasi J, Zemlin C, Vu HL, Schelonka R, Schroeder HW Jr, Mestecky J. Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire. The Journal of Virology 2007 Sep;81(17):9331-8 9. Ivanov II, McKenzie BS, Zhou L, Tadokoro C, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgt directs the differentiation program of pro-inflammatory IL-17+ T helper cells. Cell 2006, 126(6):1121-33 10. Ivanov II, Diehl GE, and Littman DR. Lymphoid Tissue Inducer Cells in Intestinal Immunity. Curr Top Microbiol Immunol 2006, 308:59-82 11. GC Ippolito, RL Schelonka, M Zemlin, Ivanov II, R Kobayashi, C Zemlin, GL Gartland, L Nitschke, J Pelkonen, K Fujihashi, K Rajewsky and HW Schroeder, Jr. Forced Usage Of Positively Charged Amino Acids In Immunoglobulin CDR-H3 Impairs B Cell Development And Antibody Production. The Journal of Experimental Medicine 2006, 203(6):1567-78 12. Ivanov II, RL Schelonka, Y Zhuang, GL Gartland, M Zemlin, and HW Schroeder, Jr. 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 2005, 174:7773-7780 13. Schelonka RL*, Ivanov II*, Jung DH, Ippolito GC, Nitschke L, Zhuang Y, Gartland GL, Pelkonen J, Alt FW, Rajewsky K, Schroeder HW Jr. 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 2005, 175:6624-32 14. Ivanov II, Link JM, Ippolito GC and Schroeder HW, Jr. Constraints on the Hydropathicity and Sequence Composition of HCDR3 are Conserved Across Evolution. In The Antibodies 2002, 7:43-67. Ed. by Zanetti M & Capra JD
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