Regulatory and helper T-cell subsets in immune-mediated diseases and cancer
CD4+ T-cells are central players of adaptive immune responses, because they co-ordinate the activity of several other immune cells 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 promote and suppress immune responses, respectively. Both regulatory and helper T-cells can produce Interleukin-10 (IL-10), which is a potent anti-inflammatory cytokine but also promotes cytotoxic T-cell responses and B-cell antibody production. Consequently, IL-10 has a dual role in autoimmunity and cancer: On the one hand it is required to maintain intestinal immune homeostasis and to prevent colitis, but on the other hand it could promote the generation of pathogenic autoantibodies in systemic lupus erythematosus (SLE). Also in cancer IL-10 might have a dual role and is thought to inhibit inflammation-driven cancer in the colon, but could promote potentially protective cytotoxic immune responses in other types of tumors.
IL-10 producing regulatory T-cells can be sub-divided into the well-defined CD25+Tregs, which express the lineage-defining transcription factor Foxp3, and the poorly defined Tr1-cells, which produce high levels of IL-10. It is unclear if also Tr1-cells represent an independent differentiation lineage or only a transient and unstable activation stage. The identification of a molecular signature of in vivo occurring Tr1-cells would clarify this key issue. Tr1-cells can play a protective role in various autoimmune diseases, but their role in cancer remains to be defined.
IL-10 is also produced by helper T-cells, but the function of helper T-cell derived IL-10 is poorly understood. We identified a population of auto-reactive CCR6+ memory T-cells in healthy individuals, which appear to have a context-dependent helper/regulatory function: IL-10 produced by these CCR6+ T-cells inhibited auto-reactive T-cell proliferation induced by myeloid DC, but it also promoted IgG production from naive B-cells. IL-10 producing CCR6+ T-cells are distinct from other known T-cell subsets like Th17-cells, Tr1-cells and follicular B helper T-cells (Tfh). They promote autoantibody production in SLE, suggesting that they play a pathogenic role. Finally, in multiple sclerosis auto-reactive CCR6+T-cells have down-regulated IL-10 and have instead up-regulated pro-inflammatory cytokines like IFN-g and GM-CSF. These auto-reactive, pro-inflammatory CCR6+ T-cells are enriched together with virus-specific Th1-cells in the cerebrospinal fluid of patients following attacks, suggesting that these two T-cell subsets promote respectively relapses and anti-viral immune surveillance in the central nervous system.
- Pathogenic versus protective roles of IL-10 producing T-cell subsets in systemic lupus erythematosus and inflammatory bowel diseases.
- Characterization of potentially pathogenic IL-17 producing T-cell subsets in multiple sclerosis and inflammatory bowel diseases.
- Identification and characterization of transcription factors and miRNAs that control the generation and function of IL-10-producing regulatory Tr1-cells.
- Regulation of cytotoxic anti-tumor T-cell responses by tumor-infiltrating Tr1-cells.
- Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells.
Gruarin P, Maglie S, De Simone M, Häringer B, Vasco C, Ranzani V, Bosotti R, Noddings JS, Larghi P, Facciotti F, Sarnicola ML, Martinovic M, Crosti M, Moro M, Rossi RL, Bernardo ME, Caprioli F, Locatelli F, Rossetti G, Abrignani S, Pagani M, Geginat J.
Eur J Immunol. 2019 Jan;49(1):96-111.
- Intestinal IFN-γ-producing Tr1-cells co-express CCR5 and PD-1, and down-regulate IL-10 in the inflamed gut of IBD patients.
Alfen JS, Larghi P, Facciotti F, Gagliani N, Bosotti R, Paroni M, Maglie S, Gruarin P, Vasco CM, Ranzani V, Frusteri C, Iseppon A, Moro M, Crosti MC, Gatti S, Pagani M, Caprioli F, Abrignani S, Flavell RA, Geginat J.
J Allergy Clin Immunol (2018) [Epub ahead of print]
- The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance?
Geginat J, Paroni M, Pagani M, Galimberti D, De Francesco R, Scarpini E, Abrignani S.
Trends Immunol (2017) 38:498-512
- 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) 140:797-808
- 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, Haringer B, Alfen JS, Penatti A, Maglie S, Paroni M, Iseppon A, Moro M, Crosti MC, Stolzel 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 (2016) 137:318-321 e5
- 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) 30:87-93
- 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) 46:1622-32
- Signal Strength and Metabolic Requirements Control Cytokine-Induced Th17 Differentiation of Uncommitted Human T Cells.
Kastirr I, Crosti M, Maglie S, Paroni M, Steckel B, Moro M, Pagani M, Abrignani S, Geginat J.
J Immunol (2015) 195:3617-27
- 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, Stolzel K, Romagnani C, Botti F, Caprioli F, Pagani M, Abrignani S, Geginat J.
J Immunol (2014) 193:3322-31
- 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) 25:252-62
- 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, Stolzel K, Torretta S, Pignataro L, Scheibenbogen C, Neddermann P, De Francesco R, Abrignani S, Geginat J.
Blood (2013) 122:932-42
- CCR6 is expressed on an IL-10-producing, autoreactive memory T cell population with context-dependent regulatory function.
Rivino L, Gruarin P, Haringer B, Steinfelder S, Lozza L, Steckel B, Weick A, Sugliano E, Jarrossay D, Kuhl AA, Loddenkemper C, Abrignani S, Sallusto F, Lanzavecchia A, Geginat J.
J Exp Med (2010) 207:565-77
- Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood.
Haringer B, Lozza L, Steckel B, Geginat J.
J Exp Med (2009) 206:1009-17