ROTRF Recognition Prize – Recognising Excellence in Organ Transplantation Research

13:55: Origin and TCR Repertoire of Allospecific CD4+Foxp3+ Regulatory T Cells

Dr Leszek Igantowicz, Medical College of Georgia, Augusta, USA

Subpopulations of regulatory CD4+ T cells that express the transcription factor Foxp3 have natural immunosuppressive properties (TR cells). These cells can differentiate from immature thymocytes in the thymus, or from naïve Foxp3- T cells in the periphery. Currently, the origin and antigen specificities of TR cells involved in the induction of tolerance to allogenic grafts are not clear. It has been postulated that thymus-derived, natural TR cells primarily recognize self-MHC/peptide complexes, preventing autoimmunity, whereas TR cells differentiating in the periphery would recognize non-self-antigens, including allo-MHC/peptide complexes. Thus, for clinical advancement, it is critical to determine if therapeutic approaches should be focused on the expansion of preexisting thymus-derived TR cells, the induction of Foxp3 expression in non-regulatory T cells, or both.

Here, we used a new mouse model (TCRmini mice) to examine the origin and antigen receptors (TCRs) on individual CD4+Foxp3- and Foxp3+ T cells. In this model, all T cells express a single TCR-ß chain paired with various TCR-α chains, derived entirely from the Vα2Jα26Jα2 mini-locus that undergoes natural rearrangements. Using this model, we show that TCRs on TR cells derived from the thymus are intrinsically more diverse than the TCRs found on naive Foxp3- T cells, and that the former subpopulation of CD4+ T cells recognize non-self MHC/peptide complexes as frequently as non-regulatory T cells. We also found that the expression of the Foxp3, which defines TR cells regulatory properties, is remarkably stable in thymus-derived TR cells, demonstrating that most of the TR cells remain committed to the regulatory function for their lifespan. TCRs expressed on these cells were often different from TCRs expressed on Foxp3- T cells, and this feature was also applicable to allospecific TR cells. In contrast, we found little evidence that a significant portion of allospecific TR cells is converted from allospecific CD4+Foxp3+ T cells in the periphery, or that this process enriches the natural TR repertoire in many new allospecific TCRs. Overall, the results of our research emphasize the significance of thymus-derived, natural TR cells, and suggest that future therapeutic protocols should be focused on the expansion of the preexisting TR cells, rather than the TR ex vivo differentiation. This research is particularly relevant to the future design of clinical protocols, which will utilize the adaptive transfer of expanded host TR cells to enhance tolerance induction and prevent chronic graft rejection.

Leszek Igantowicz

Dr Leszek Ignatowicz is currently appointed as a Professor in the Center for Biotechnology and Genomic Medicine, at the Medical College of Georgia, USA. After receiving his PhD in Immunology from the Institute for Immunology in Poland, he moved to the US in 1990 to attend post-doctoral training at the National Jewish Center in Denver, Colorado. As a post-doctoral fellow he generated the first “single MHC/peptide” mouse where all class II MHC molecules are bound with one, covalently linked peptide. In 1996, he moved to Augusta, GA (Medical College of Georgia), where he was appointed as faculty and has continued his research on the development and antigen specificities of CD4+ T cells. Recently, his research has been focused on the role of CD4+Foxp3+ regulatory T cells in the regulation of immunoresponse to self and non-self antigens. He has published over 50 articles in peer-reviewed journals. He is a member of the American Association of Immunologists and has served as a referee for the National Institutes of Health, National Science Foundation, and Veterans Administration, and several journals including Immunity, Proceedings of the National Academy of Sciences, Journal of Experimental Medicine, and Journal of Immunology.