Maria-Grazia Roncarolo

San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) and Vita-Salute San Raffaele University, Milan, Italy

Title: The Interplay Between Natural Treg and Tr1 Cells

Authors: Kevin Goudy¹, Silvia Gregori¹, Manuela Battaglia¹, Rosa Bacchetta¹, Nicola Gagliani¹, and Maria-Grazia Roncarolo¹,²
¹San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; ²Vita-Salute San Raffaele University, Milan, Italy

The immune system has evolved to create a diverse population of regulatory T cells capable of controlling auto-reactivity and resolving pathogenic immunological events. Notably, the naturally occurring Treg (nTreg) cells and the IL-10-producing type 1 regulatory (Tr1) cells are considered to be among the most potent regulatory cells. Although these two cell subsets work in harmony to maintain immune homeostasis they are believed to be developmentally and functionally distinct.

nTreg cells develop solely in the thymus when the expression of the transcription factor FoxP3 is induced after self-antigen (Ag) recognition. Conversely, Tr1 cells develop in the periphery upon chronic Ag-stimulation in the presence of IL-10 derived from tolerogenic APC, resulting in Ag-specific T cells with the capacity to produce high levels of IL-10 in the absence of IL-4. Furthermore, Tr1 cells are distinct from nTreg as they do not express FoxP3, and can freely develop in its absence as demonstrated by the identification of Tr1 cells in IPEX patients who encode for a defective form of the FoxP3 protein. Despite normal Tr1 cell development, systemic autoimmune syndromes affect IPEX patients indicating that Tr1 cells are not sufficient to inhibit overt autoimmune manifestations. On the other hand, deficiencies in IL-10 production or Tr1 cells leads to excessive immune responses against foreign Ags resulting in significant host pathology.

Despite the disparity of function and origin of nTreg and Tr1 cells, new evidence from our lab suggests that nTreg can play a role in the development of Tr1 cells possibly through infectious tolerance. Transfer of nTreg cells from tolerant mice after allogeneic islet transplantation can induce graft tolerance in new recipient mice by inducing Tr1 cells. The results suggest that although nTreg and Tr1 cells play nonredundant roles in immune homoeostasis, it is possible that the interplay between nTreg and Tr1 forms during a robust immune reaction whereby nTreg drive the development of Tr1 cells for the long-term maintenance to foreign Ag.

Keywords:
Tr1, tolerance, transplantation, nTreg

Biography:

Maria Grazia Roncarolo is the Scientific Director of the San Raffaele Scientific Institute in Milan, Italy, and Professor in Pediatrics, School of Medicine and Surgery, San Raffaele Vita-Salute University, in Milan.

She is a M.D., specialized in Pediatrics and Immunology. Since July 2003, she is Chief of Clinic, Pediatric Immunology and Hematology and Clinical Research Unit (CRU-P), San Raffaele Hospital and San Raffaele Scientific Institute.

She worked in Lyon for several years at the Edouard Herriot Hospital and at the Laboratory for Immunological Research UNICET on the mechanism of tolerance in severe combined immunodeficiency (SCID) patients transplanted with allogenic hematopoietic stem cells.

She worked for more than 8 years at the DNAX Research Institute of Molecular and Cellular Biology, Human Immunology Department, in Palo Alto, CA, on the basic biology of hematopoietic stem cells, cytokines, and transplantation tolerance.

Since 1998 she has been working at San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), of which she has been Director from 2000 until September 2008.
She has a long-lasting interest in the mechanisms, which induce and maintain tolerance in bone marrow transplantation, organ transplantation, autoimmune disease and gene therapy.

In addition, she is interested in investigating the mechanisms underlying the immune defects, and identifying new cures for children with severe combined immunodeficiency (SCID) and other forms of primary immunodeficiencies. She studied the mechanism of tolerance in SCID patients transplanted with allogenic hematopoietic stem cells. In these children, she demonstrated that tolerance is due to an active mechanism of suppression. She was among the first to convincingly prove that active suppression is mediated by regulatory T cells. Her group was pioneer in the demonstration and biological characterization of a new subset of regulatory T cells named T regulatory type 1. Since her publication in the “Nature” scientific journal, these cells have been the subject of extensive investigation, and several groups, including that of Maria Grazia Roncarolo, proved that T regulatory type 1 cells play a key role in immunological homeostasis and in prevention of autoimmune diseases.

In 2000, Maria Grazia Roncarolo has been awarded the honor of Ufficiale dell’Ordine “Al Merito della Repubblica Italiana” for scientific merits. In 2005 she has been elected member of the Academia Europaea of Sciences. Maria Grazia Roncarolo is among the world’s most cited scientists according to ISIHighlyCited.com (Thomson Reuters, Philadelphia). She has published 210 papers in international scientific peer review journals (total Impact Factor 2106 with average I.F. 10,03), and contributed 22 chapters to books. Overall, her papers have been cited > 9250 times. (Scopus “h “ index : 52). Inventor of 11 international patents issued or pending.

Her current research and clinical interests are:

Research Interests:

• Immunotolerance:  Mechanisms underlying T-cell tolerance, induction of T-cell anergy and T regulatory cells.
• Immunomodulation: Mechanisms underlying T-cell activation and T-cell anergy
• Transplantation: Immune reconstitution and T-cell tolerance after allogenic stem cell transplantation
• Primary immunodeficiencies: Characterization of molecular and immunological defects
• Hematopoiesis: Mechanisms underlying growth and differentiation of hematopoietic precursors
• Cytokines: Role in regulation of immune and inflammatory responses
• Gene therapy: Gene transduction of hematopoietic stem cells for gene therapy in primary immunodeficiencies and metabolic diseases

Clinical Interests:

• Primary immunodeficiencies
• Autoimmune diseases
• Allogenic Bone Marrow Transplantation
• Gene Therapy Clinical trials
• Hemoglobinopathies