Department and institution: Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi” INGM, Head Autoimmunity Program
Keywords related: regulatory T cells, dendritic cells, Th17 cells, Interleukin-10, autoimmune diseases
We are interested in human T cell differentiation. In particular, we study the biology of regulatory and helper T cell subsets, and assess their roles in different autoimmune diseases.
The major focus of the lab is T-cells that secrete the anti-inflammatory cytokine IL-10. We previously identified IL-10 producing regulatory (Tr1) cells directly in human blood (Haringer J. Exp. Med. 2009), and we are currently analyzing their molecular regulation by transcription factors and miRNAs. Our results suggest that Tr1-cells have a protective role in different autoimmune diseases, including inflammatory bowel diseases (IBD) and systemic lupus erythematosus (SLE), where IL-10 has non-redundant protective and pathogenic roles, respectively. Paradoxically, IL-10 can also have positive roles in immune responses and autoimmune diseases. We therefore also analyze the role of an auto-reactive, IL-10 producing memory T-cell subset that we have identified previously (Rivino, J. Exp. Med 2010) in SLE, to understand if these helper T-cells might induce pathogenic autoantibodies via IL-10. Finally, we are participating in a clinical trial to evaluate the effects of therapeutic IL-10 neutralization on different immune cells in SLE patients.
We are also interested in human DC subsets, because they are the physiological inducers of T-cell differentiation. We have shown previously that conventional CD1c+ dendritic cells (DC) can cross-prime cytotoxic T-cell (CTL) responses (Nizzoli, Blood 2013). More recently, we have analyzed the regulation of IL-10 production in DC subsets, and the different roles of DC-derived IL-10 on CTL priming and memory maintenance.
A second focus of the lab is the generation and function of Th17 cells that co-produce IL-17 and other pro-inflammatory cytokines, because these cells are the major drivers of autoimmunity in mouse models, but are poorly defined in humans. We have identified the unique signal strength and metabolic requirements to induce human Th17 cells from uncommitted precursors, and we have shown that IL-21 regulates the balance between conventional and pathogenic Th17 cells (Kastirr, J Immunol. 2014). In autoimmune enteropathy (AIE) we are studying the induction of unconventional IL-17 and IFN--co-producing intraepithelial lymphocytes (IEL). Finally, we have identified different subsets of potentially pathogenic human Th17 cells, which are selectively associated with Multiple sclerosis (MS) and inflammatory bowel disease (IBD), respectively. The conditions that lead to the generation of these subsets, as well as their properties that contribute to their selective pathogenicity in MS or IBD are under current investigation.
Lab / Research Group Link: http://www.ingm.org/en/research/research-projects/autoimmunity
1. IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells. I. Kastirr, S. Maglie, M. Paroni, J.S. Alfen, G. Nizzoli, E. Sugliano , MC. Crosti, M. Moro, B. Steckel, S. Steinfelder, K. Stölzel, C. Romagnani, F. Botti, F. Caprioli, M. Pagani, S. Abrignani, J. Geginat. The Journal of Immunology (IF 5.36) 2014, 193(7): 3322-31
2. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T cell responses G. Nizzoli, J. Krietsch*, A. Weick*, S. Steinfelder*, F. Facciotti, P.Gruarin, A. Bianco, B. Steckel, M. Moro, M.C. Crosti1, C. Romagnani, K. Stölzel, S. Torretta, L. Pignataro, C. Scheibenbogen, P. Neddermann, R. DeFrancesco, S. Abrignani, J. Geginat. Blood (IF 9.78), 2013, 122(6): 932-42
3. The CD4-centred universe of human T cell subsets. J. Geginat, M. Paroni, F. Facciotti, P. Gruarin, I. Kastirr, F. Capriolo, M. Pagani, S. Abrignani. Seminars in Immunology (IF 6.12) 2013, 25(4):252-62
4. Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. S. Steinfelder, S. Floess, U. Baron, L. Rivino, B. Häringer, B. Steckel, A. Gruetzkau, S. Olek, J. Geginat°, J. Hühn°, and A. Hamann° (° equal contributions). Blood (IF 9.78), 2011, 117(10):2839-46
5. CCR6 is expressed on an IL-10 producing, auto-reactive memory T cell population with context-dependent regulatory function L. Rivino, P. Gruarin, B. Häringer, S. Steinfelder, L. Lozza, E. Sugliano, A. Weick, D. Jarrossay, A. Kuehl, C. Loddenkemper, S. Abrignani, F. Sallusto, A. Lanzavecchia and J. Geginat. The Journal of Experimental Medicine (IF 13.9), 2010, 207(3): 565-577