Pathogenic and Regulatory T Cells in Type 1 Diabetes: Losing Self-Control, Restoring It, and How to Take the Temperature
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The central role of T cells in type 1 diabetes pathogenesis is well established, but these cells continue to pose numerous challenges in understanding their dynamics and in following their modifications. Important progress has been recently made in pinpointing some novel antigens targeted by pathogenic T cells and the epitope sequences recognized. Studies on the interplay between effector T cells, their regulatory counterparts, and cells of the innate immune system have unraveled novel pathways and may inspire new therapeutic approaches. At the same time, the appreciation of the plasticity of regulatory T cells has raised important caveats on their use for cell-based therapies. Continuous development of T-cell assays exploring both pathogenic and regulatory players will be critical to “take the temperature” of undergoing disease progression and reversal.
KeywordsEpitopes Innate immunity Peripheral tolerance T-cell assays Type 1 diabetes
Work performed in the laboratory is supported by the Juvenile Diabetes Research Foundation (JDRF grant no. 1-2008-106), European Foundation for the Study of Diabetes (EFSD), and Lilly European Diabetes Research Program, Programme Blanc “Immunotolerins” of the Agence Nationale de la Recherche and by the INSERM Avenir program. We gratefully acknowledge Anna Falaschi-Jones for editorial assistance.
No potential conflicts of interest relevant to this article were reported.
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- 3.•• Skowera A, Ellis RJ, Varela-Calvino R, et al. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J Clin Invest 2008;118:3390–2. This study shows that a PPI epitope derived from the signal peptide is targeted by diabetogenic T cells and that its processing and presentation by β cells is regulated by glucose concentrations.PubMedGoogle Scholar
- 10.Dang M, Rockell J, Wagner R, et al. Human Type 1 diabetes is associated with T cell autoimmunity to zinc transporter 8. J Immunol. 2011;186:6056–63Google Scholar
- 11.•• Stadinski BD, Delong T, Reisdorph N, et al. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol 2010;11:225–31. This paper identifies the target epitope of the diabetogenic CD4+ T-cell clone BDC2.5 isolated from NOD mice. This epitope is complexed with I-Ag7 with an unusual binding registry.PubMedCrossRefGoogle Scholar
- 15.• Grinberg-Bleyer Y, Saadoun D, Baeyens A, et al. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J Clin Invest 2010;120:4558–68. Teffs can boost the expansion and suppressive activity of Tregs, revealing a novel crosstalk pathway in diabetes development and protection.PubMedCrossRefGoogle Scholar
- 19.Grinberg-Bleyer Y, Baeyens A, You S, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med 2010;207:1871–8.Google Scholar
- 24.• Jiang H, Canfield SM, Gallagher MP, et al. HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. J Clin Invest 2010;120:3641–50. This paper provides proof that a human HLA-E-restricted CD8+ T-cell subset displays a regulatory role in the periphery and proposes an avidity mechanism of peripheral tolerance that is altered in T1D.PubMedCrossRefGoogle Scholar
- 25.• Diana J, Brezar V, Beaudoin L, et al. Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay. J Exp Med 2011 208:729–45. The interaction between innate and adaptive immune cells is dissected to explain its opposing role in mounting viral-specific responses and in blunting autoimmunity in mouse models.PubMedCrossRefGoogle Scholar
- 36.• Zhou X, Bailey-Bucktrout SL, Jeker LT, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009;10:1000–7. This paper supports the notion of plasticity of murine Tregs, which can convert into pathogenic Teffs in vivo.PubMedCrossRefGoogle Scholar
- 48.Mallone R, Mannering SI, Brooks-Worrell BM, et al. Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses: position statement of the T-Cell Workshop Committee of the Immunology of Diabetes Society. Clin Exp Immunol. 2011;163:33–49.PubMedCrossRefGoogle Scholar
- 49.Brooks-Worrell B, Tree T, Mannering SI, et al. Comparison of cryopreservation methods on T cell responses to islet and control antigens from type 1 diabetes patients and controls. Diabetes Metab Res Rev 2011, in press.Google Scholar
- 52.Mallone R, Scotto M, Janicki CN, et al. Immunology of Diabetes Society T-cell workshop: HLA class I tetramer-directed epitope validation initiative. Diabetes Metab Res Rev 2011; In press.Google Scholar
- 53.James EA, Mallone R, Schloot NC, et al. Immunology of Diabetes Society T-cell workshop: HLA class II tetramer-directed epitope validation initiative. Diabetes Metab Res Rev 2011; In press.Google Scholar
- 54.• Fourlanos S, Perry C, Gellert SA, et al. Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 2011;60:1237–45. This paper is the first to document Ag-specific tolerance restoration both at the T-cell and antibody level following intranasal insulin administration in T1D patients.PubMedCrossRefGoogle Scholar
- 55.Martinuzzi E, Afonso G, Gagnerault MC, et al. Accelerated co-cultured dendritic cells (acDCs) enhance human antigen-specific T-cell responses. Blood 2011; doi: 10.1182/blood-2010-12-326231