Autoimmunity

 

Team

Bosotti Roberto, Graduate Fellow, bosotti@ingm.org
Larghi Paola, Post-doc larghi@ingm.org
Paroni Moira, Post-doc paroni@ingm.org

Scientific Background

CD4+ T cells are central players of adaptive immune responses, because they co-ordinate the activity of several other immune cell subsets such as dendritic cells (DC), B cells and cytotoxic CD8+ T cells. CD4+ T cells can be subdivided into two broad subset of helper and regulatory cells, which respectively promote and suppress immune responses, and consequently have opposing roles in autoimmunity. Both regulatory and helper T cells produce Interleukin-10 (IL-10), which is a potent anti-inflammatory cytokine but It also promotes cytotoxic T cell and B cell responses. Consequently, IL-10 has a dual role in autoimmunity in mice and humans: On the one hand it is required to maintain intestinal immune homeostasis and to prevent colitis, but on the other hand it promotes the generation of pathogenic autoantibodies and nephritis in systemic lupus erythematosus. IL-10 producing regulatory T cells can be further sub-divided into the well-defined CD25+ Tregs, which express the lineage-defining transcription factor Foxp3, and the poorly characterized Tr1 cells. Human Tr1 cells are difficult to identify in vivo and it is therefore unclear if they represent an independent differentiation lineage as CD25+ Tregs, or only a transient and unstable activation stage. The identification of specific surface markers and transcription factors of in vivo occurring Tr1 cells would be a milestone to clarify this issue. IL-10 is also produced by monocytes and dendritic cells, and DC-derived IL-10 could induce suppressive Tr1 cells on the one hand, but promote CD8+ cytotoxic T cell responses on the other hand. Moreover, IL-10 inhibits IL-17 producing T helper (Th17) cells, which have a pathogenic role in autoimmune diseases when they acquire characteristics of Th1 cells and thus co-produce several pro-inflammatory cytokines including IL-17, IFN- and GM-CSF. How these pathogenic Th1/17 cells are generated is incompletely understood in humans, and their role in autoimmune diseases remains to be defined.

Ongoing Projects

  1. Pathogenic versus protective roles of IL-10 producing T-cell subsets in systemic lupus erythematosus and inflammatory bowel diseases.
  2. Characterization of potentially pathogenic IL-17 producing T-cell subsets in multiple sclerosis and inflammatory bowel diseases.
  3. Identification and characterization of transcription factors and miRNAs that control the generation and function of IL-10-producig regulatory T-cells.
  4. Regulation of cytotoxic anti-tumor T-cell responses by dendritic cells and IL-10.

Related Publications

CD4+ T Helper Cell Plasticity in Infection, Inflammation, and Autoimmunity.
Huber S, Gagliani N, O’Connor W Jr, Geginat J, Caprioli F.
Mediators Inflamm. 2017;2017:7083153. doi: 10.1155/2017/7083153. Epub 2017 Jan 29.

Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.
Paroni M, Maltese V, De Simone M, Ranzani V, Larghi P, Fenoglio C, Pietroboni AM, De Riz MA, Crosti MC, Maglie S, Moro M, Caprioli F, Rossi R, Rossetti G, Galimberti D, Pagani M, Scarpini E, Abrignani S, Geginat J.
J Allergy Clin Immunol. 2017 Feb 16. pii: S0091-6749(17)30043-X. doi: 10.1016/j.jaci.2016.11.045. [Epub ahead of print]

Reverse plasticity: TGF- β and IL-6 induce Th1-to-Th17-cell transdifferentiation in the gut
Geginat J, Paroni M, Kastirr I, Larghi P, Pagani M, Abrignani S.
Eur. J. Immunol. 2016. 46: 2306–2310

Uncontrolled IL-17 Production by Intraepithelial Lymphocytes in a Case of non-IPEX Autoimmune Enteropathy.
Paroni M, Magarotto A, Tartari S, Nizzoli G, Larghi P, Ercoli G, Gianelli U, Pagani M, Elli L, Abrignani S, Conte D, Geginat, Caprioli F.
NClin Transl Gastroenterol. 2016 Jul 14;7(7):e182. doi: 10.1038/ctg.2016.41.

The adipose mesenchymal stem cell secretome inhibits inflammatory responses of microglia: evidence for an involvement of sphingosine-1-phosphate signalling
Marfia G, Navone SE, Abdel Hadi L, Paroni M, Berno V, Beretta M, Gualtierotti R, Ingegnoli F, Levi V, Miozzo M, Geginat J, Fassina L, Rampini P, Tremolada C, Riboni L, Campanella R.
Stem Cells Dev. 2016 May 23. [Epub ahead of print]

IL-10 promotes homeostatic proliferation of human CD8+ memory T cells and, when produced by CD1c+ DCs, shapes naive CD8+ T-cell priming.
Nizzoli G, Larghi P, Paroni M, Crosti MC, Moro M, Neddermann P, Caprioli F, Pagani M, De Francesco R, Abrignani S, Geginat J.
Eur J Immunol. 2016 Apr 30. doi: 10.1002/eji.201546136. [Epub ahead of print]

The light and the dark sides of Interleukin-10 in immune-mediated diseases and cancer
Geginat J, Larghi P, Paroni M, Nizzoli G, Penatti A, Pagani M, Gagliani N, Meroni P, Abrignani S, Flavell RA.
Cytokine Growth Factor Rev. 2016 Mar 8. pii: S1359-6101(16)30019-3. doi: 10.1016/j.cytogfr.2016.02.003. [Epub ahead of print]

Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets.
Geginat J, Nizzoli G, Paroni M, Maglie S, Larghi P, Pascolo S, Abrignani S.
Front Immunol. 2015 Oct 13;6:527. doi: 10.3389/fimmu.2015.00527. eCollection 2015. Review.

Signal Strength and Metabolic Requirements Control Cytokine-Induced Th17 Differentiation of Uncommitted Human T Cells
Kastirr I, Crosti MC, Maglie S, Paroni M, Steckel B, Moro M, Pagani M, Abrignani S, Geginat J
Journal of Immunology. Sept 2015

IL-10-producing forkhead box protein 3-negative regulatory T cells inhibit B-cell responses and are involved in systemic lupus erythematosus.
Facciotti F, Gagliani N, Häringer B, Alfen JS, Penatti A, Maglie S, Paroni M, Iseppon A, Moro M, Crosti MC, Stölzel K, Romagnani C, Moroni G,Ingegnoli F, Torretta S, Pignataro L, Annoni A, Russo F, Pagani M, Abrignani S, Meroni P, Flavell R, Geginat J.
J Allergy Clin Immunol. 2015 Aug 25. pii: S0091-6749(15)00999-9. doi: 10.1016/j.jaci.2015.06.044. [Epub ahead of print]

Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.
Gagliani N, Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva R, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA.
Nature. 2015 Apr 29. doi: 10.1038/nature14452. [Epub ahead of print]

The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4.
Ranzani V, Rossetti G, Panzeri I, Arrigoni A, Bonnal RJP, Curti S, Provasi E, Sugliano E, De Francesco R, Geginat J, Bodega B, Abrignani S, Pagani M.
Nat Immunol. 2015; 16: 318-25.

Plasticity of human CD4 T cell subsets.
Geginat J, Paroni M, Maglie S, Alfen JS, Kastirr I, Gruarin P, De Simone M, Pagani M, Abrignani S.
Front Immunol. 2014 Dec 16;5:630. doi: 10.3389/fimmu.2014.00630. eCollection 2014.

IL-21 Is a Central Memory T Cell-Associated Cytokine That Inhibits the Generation of Pathogenic Th1/17 Effector Cells.
Kastirr I, Maglie S, Paroni M, Alfen JS, Nizzoli G, Sugliano E, Crosti MC, Moro M, Steckel B, Steinfelder S, Stölzel K, Romagnani C, Botti F, Caprioli F, Pagani M, Abrignani S, Geginat J
J Immunol. 2014 Oct 1;193(7):3322-31.

Absence of a role for interleukin-13 in inflammatory bowel disease
Biancheri P, Di Sabatino A, Ammoscato F, Facciotti F, Caprioli F, Curciarello R, Hoque SS, Ghanbari A, Joe-Njoku I, Giuffrida P, Rovedatti L, Geginat J, Corazza GR, MacDonald TT.
Eur J Immunol. 2014 Feb;44(2):370-85. doi: 10.1002/eji.201343524.

Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation
de Candia P, Torri A, Gorletta T, Fedeli M, Bulgheroni E, Cheroni C, Marabita F, Crosti M, Moro M, Pariani E, Romanò L, Esposito S, Mosca F, Rossetti G, Rossi RL, Geginat J, Casorati G, Dellabona P, Pagani M, Abrignani S.
PLoS One. 2013 Sep 26;8(9):e75348. doi: 10.1371/journal.pone.0075348. eCollection 2013.

The CD4-centered universe of human T cell subsets
Geginat J, Paroni M, Facciotti F, Gruarin P, Kastirr I, Caprioli F, Pagani M, Abrignani S.
Semin Immunol. 2013 Nov 15;25(4):252-62. doi: 10.1016/j.smim.2013.10.012. Epub 2013 Nov 1.

Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses
Nizzoli G, Krietsch J, Weick A, Steinfelder S, Facciotti F, Gruarin P, Bianco A, Steckel B, Moro M, Crosti M, Romagnani C, Stölzel K, Torretta S, Pignataro L, Scheibenbogen C, Neddermann P, De Francesco R, Abrignani S, Geginat J.
Blood. 2013 Aug 8;122(6):932-42. doi: 10.1182/blood-2013-04-495424. Epub 2013 Jun 21.

Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation
Pagani M, Rossetti G, Panzeri I, de Candia P, Bonnal RJ, Rossi RL, Geginat J, Abrignani S.
Immunol Rev. 2013 May;253(1):82-96. doi: 10.1111/imr.12055. Review.

Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis
Zingaretti C, Arigò M, Cardaci A, Moro M, Crosti M, Sinisi A, Sugliano E, Cheroni C, Marabita F, Nogarotto R, Bonnal RJ, Marcatili P, Marconi M, Zignego A, Muratori P, Invernizzi P, Colombatto P, Brunetto M, Bonino F, De Francesco R, Geginat J, Pagani M, Muratori L, Abrignani S, Bombaci M.
Mol Cell Proteomics. 2012 Dec;11(12):1885-97. doi: 10.1074/mcp.M112.018713. Epub 2012 Sep 20.

Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b
Rossi RL, Rossetti G, Wenandy L, Curti S, Ripamonti A, Bonnal RJ, Birolo RS, Moro M, Crosti MC, Gruarin P, Maglie S, Marabita F, Mascheroni D, Parente V, Comelli M, Trabucchi E, De Francesco R, Geginat J, Abrignani S, Pagani M.
Nat Immunol. 2011 Jun 26;12(8):796-803. doi: 10.1038/ni.2057.

Dual role of anti-TNF therapy: enhancement of TCR-mediated T cell activation in peripheral blood and inhibition of inflammation in target tissues
Bosè F, Raeli L, Garutti C, Frigerio E, Cozzi A, Crimi M, Caprioli F, Scavelli R, Altomare G, Geginat J, Abrignani S, Reali E.
Clin Immunol. 2011 May;139(2):164-76. doi: 10.1016/j.clim.2011.01.015. Epub 2011 Jan 31.

Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells
Steinfelder S, Floess S, Engelbert D, Haeringer B, Baron U, Rivino L, Steckel B, Gruetzkau A, Olek S, Geginat J*, Huehn J*, Hamann A*. (* equal contributions)
Blood. 2011 Mar 10;117(10):2839-46. doi: 10.1182/blood-2010-06-293027. Epub 2011 Jan 12.

Biology of interleukin-10
Sabat R, Grütz G, Warszawska K, Kirsch S, Witte E, Wolk K, Geginat J.
Cytokine Growth Factor Rev. 2010 Oct;21(5):331-44. doi: 10.1016/j.cytogfr.2010.09.002. Epub 2010 Nov 5. Review.

CCR6 is expressed on an IL-10-producing, autoreactive memory T cell population with context-dependent regulatory function
Rivino L, Gruarin P, Häringer B, Steinfelder S, Lozza L, Steckel B, Weick A, Sugliano E, Jarrossay D, Kühl AA, Loddenkemper C, Abrignani S, Sallusto F, Lanzavecchia A, Geginat J.
J Exp Med. 2010 Mar 15;207(3):565-77. doi: 10.1084/jem.20091021. Epub 2010 Mar 1.

Human bone marrow as a source to generate CMV-specific CD4+ T cells with multifunctional capacity
Na IK, Letsch A, Guerreiro M, Bauer S, Noack I, Geginat J, Reinke P, Loesch M, Kienapfel H, Thiel E, Volk HD, Scheibenbogen C.
J Immunother. 2009 Nov-Dec;32(9):907-13. doi: 10.1097/CJI.0b013e3181b7be60.

Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood
Häringer B, Lozza L, Steckel B, Geginat J.
J Exp Med. 2009 May 11;206(5):1009-17. doi: 10.1084/jem.20082238. Epub 2009 May 4.

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