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.

Projects

  • 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.

Team

Nome / NameRuolo / RoleEmail
Roberto BosottiGraduate Fellowbosotti@ingm.org
Elisabetta BulgheroniLaboratory Technicianbulgheroni@ingm.org
Bhavna KarnaniGraduate Fellowkarnani@ingm.org
Nadia PulvirentiGraduate Fellowpulvirenti@ingm.org
Maria Chiara VascoPost Docvasco@ingm.org

Publications

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