Submitted Successfully!
Thank you for your contribution! You can also upload a video entry related to this topic through the link below: https://encyclopedia.pub/user/video_add?id=20946
Check Note
2000/2000
Ver. Summary Created by Modification Content Size Created at Operation
1 + 2287 word(s) 2287 2022-03-22 04:38:58 |
2 update layout and reference Meta information modification 2287 2022-03-24 03:37:27 | |
3 update layout Meta information modification 2287 2022-03-25 07:20:20 | |
4 update layout + 1 word(s) 2288 2022-03-25 07:57:58 |
Regulatory T Cells in Type 1 Diabetes
Edit
Upload a video

Type 1 diabetes (T1D) is an autoimmune disease that typically presents in childhood and early adulthood that results in the destruction of insulin-producing pancreatic beta cells by T cells. One potential protective mechanism includes the suppression of immune responses by regulatory CD4 T cells (Tregs) that recognize self-peptides from islets presented by human leukocyte antigen (HLA) class II molecules.

regulatory T cells type 1 diabetes islet autoimmunity
Information
Subjects: Immunology
Contributor :
View Times: 134
Revisions: 4 times (View History)
Update Date: 25 Mar 2022
Table of Contents

    1. Introduction

    The primary pathological presentation of T1D is inflammation of the pancreatic islets, termed insulitis, and it is due to the infiltration of immune cells, including CD4 and CD8 T cells along with B cells [1][2][3][4][5][6]. Therefore, there is a direct link between pathogenic T cells targeting insulin-producing pancreatic beta cells; however, regulatory T cells (Tregs) play an important role in protection from autoimmunity, including T1D. During T1D development, there is likely an imbalance between pathogenic T cells targeting pancreatic islets and Tregs that function to protect against targeting these cells.
    The incidence of T1D continues to increase globally across racial and ethnic groups [7]. However, the measurement of T1D-associated antibodies in the peripheral blood allows for the prediction of disease progression through stages, as islet autoantibodies precede the development of clinical diabetes, in general, by a number of years [8][9][10]. Furthermore, a recent study has shown that short-term immunotherapy with an anti-CD3 monoclonal antibody can delay the onset of clinical disease [11], which is marked by hyperglycemia and the need for exogenous insulin treatment. Despite these clinically meaningful successes, there is a strong need in the field to specifically induce tolerance to islet antigens prior to and at disease onset.

    2. T Cell Receptor–Peptide–MHC Interactions

    T cells possess T cell receptors (TCRs) that recognize peptides bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) such as B cells, dendritic cells, and macrophages. TCRs consist of an alpha chain and beta chain that are generated via the recombination of noncontiguous gene segments for each chain. Both chains of the TCR include a variable (V), joining (J), and constant region, while the beta chain also contains a diversity (D) region. Therefore, the process by which TCRs are rearranged into fully functional receptors is known as V(D)J recombination. In this manner, each T cell generates a unique receptor for the recognition of a closely related set of peptides presented in the context of the MHC molecule. The interaction between TCR/peptide/MHC leads to activation of the T cells, and two major classes of T cells are involved in an adaptive immune response. Both classes recognize peptide/MHC, and cluster of differentiation 4 (CD4) T cells release cytokines to activate other immune cells and also interact with and activate B cells, while CD8 T cells act to directly kill target cells. CD4 cells can generally be subdivided into T helper type 1 (Th1) and type 2 (Th2) cells, which are distinguished by the functions and cytokine production. Th1 cells are considered proinflammatory due to the production of the cytokines interleukin-2 (IL-2) and interferon gamma (IFN-γ). Th1 cells function to direct immune responses against intracellular viral and bacterial pathogens. Th2 cells are considered more anti-inflammatory and produce the cytokines IL-4, IL-5, and IL-13 to generate immune responses directed against extracellular pathogens. Regulatory T cells (Tregs) are another subtype of CD4 T cells that suppress immune responses via multiple mechanisms, including the secretion of anti-inflammatory cytokines (e.g., IL-10 and transforming growth factor beta (TGF-β)), the expression of regulatory cell surface receptors (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)), and the direct killing of APCs via perforin and granzyme B.
    T cells are directly involved in the immunopathogenesis of T1D, and the link between autoimmunity and particular MHC alleles has been well established. In fact, numerous studies have demonstrated that MHC is the major genetic determinant for T1D [12][13][14][15][16][17][18][19][20]. Conversely, the presence of diabetes-resistant MHC alleles in transgenic mouse models can both induce the deletion of autoreactive T cells and also promote the development of Tregs [15][16][17]. Therefore, the MHC genotype may determine the balance between proinflammatory and anti-inflammatory responses to a given self-antigen. In humans, MHC proteins are encoded by the human leukocyte antigen (HLA) genes, and variants of these genes can confer significant disease risk or protection from autoimmune diseases, including T1D [21]. For example, individuals with the HLA-DQ8 (DQB1*03:02) allele have an odds ratio for T1D development of 11, while those with HLA-DQ6 (DQB1*06:02) are protected from T1D with an odds ratio of only 0.03 [22][23][24]. T1D research has primarily been focused on identifying peptides that activate T cells via presentation by diabetes risk MHC class II molecules [25]. However, little is known about the mechanisms by which protective MHC molecules provide dominant protection from T1D development.

    3. Immunologic Tolerance by Regulatory T Cells

    Two types of Tregs include thymus-derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs). nTregs express the transcription factor forkhead box P3 (Foxp3) and suppress other T cell subsets during inflammation, whereas iTregs are conventional T cells that are induced to express Foxp3 and become regulatory in peripheral lymphoid tissues. A subtype of iTreg cells, known as type 1 regulatory (Tr1) cells, do not express high levels of Foxp3 but rather CD49b and lymphocyte-activation gene 3 (LAG-3) and are able to produce high levels of both IL-10 and TGF-β [26][27]. Thus, Tr1 cells are potent suppressors of other T cell subsets via cytokine-mediated mechanisms. However, Tr1 cells can also mediate suppression via granzyme-mediated killing in a cell contact-dependent fashion [28]. Distinct subtypes of Tr1 cells have now been identified in both humans and mice, and the subtypes differ primarily in the cytokine secretion profiles [29].
    Tregs are not only important for the return to a homeostatic state after an immune response, but they are also critical for the prevention of autoimmunity. For example, Tregs induce tolerance in the periphery by suppressing autoreactive T cells that are specific for self-tissues. However, the precise molecular mechanisms by which Tregs suppress auto-antigen-specific T cells are unknown, and it is of interest to determine which antigens are being recognized by Tregs to prevent autoimmunity. It is appreciated that T1D patients do not lack overall numbers of Tregs but likely have a functional defect in bulk Tregs, which contributes to disease development [30][31][32][33]. However, researchers will focus on studies that identified and evaluated islet antigen-specific Tregs in autoimmune T1D.

    4. Antigen-Specific Tregs in Type 1 Diabetes

    Although the deletion of most autoreactive T cells occurs in the thymus, self-reactive T cells do escape and are able to circulate in the periphery [34]. These escaped self-reactive T cells can be controlled by Tregs as one mechanism of peripheral tolerance. Determining the specificity of these Tregs may aid in understanding the mechanisms involved in the loss of tolerance to self-antigens that occurs during autoimmunity and identifying specific antigens and epitopes that may be utilized for antigen-specific immunotherapy to treat the underlying autoimmunity.
    In T1D, Kwok et al. showed that islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T cells from healthy individuals and those with T1D could produce both proinflammatory (i.e., IFN-γ) and anti-inflammatory (i.e., IL-10) cytokines, indicating that antigen-specific Th1 cells and Tregs are present in the peripheral blood [35]. The IGRP-specific T cells were detected using HLA-DR4 and -DR3 tetramers, and therefore, they were of high avidity for peptide/MHC. However, because both pro- and anti-inflammatory IGRP-specific T cells were present in healthy individuals in addition to T1D patients, the results indicate that the escape of high avidity self-reactive T cells is not sufficient to cause disease. Likely, there is an imbalance in the pathogenic CD4 T cells and protective Tregs, as measured by pro- and anti-inflammatory cytokine responses, to islet self-antigens that skews the response during T1D development with a threshold needing to be met for autoreactive T cells to target pancreatic islets.
    Data in support of a cytokine imbalance toward self-antigens come from studies in the researchers' laboratory that measured cytokine responses to native and mutated insulin B chain peptides using a cytokine enzyme linked immunospot (ELISPOT) assay with peripheral blood immune cells from new-onset T1D patients as well as non-diabetic controls [36]. Importantly, the majority of individuals in both groups were carrying at least one diabetes-risk HLA allele (e.g., DQ8 or DQ2). The strongest proinflammatory T cell responses were found in response to a mutated insulin peptide—much more than the native peptide sequence. The amino acid substitution in the mutated insulin B chain peptide (B22R→E) allows the peptide to bind in an otherwise unfavorable register to T1D-risk HLA molecules (i.e., DQ8 and DQ2). In addition, anti-inflammatory responses were present in the vast majority of the non-diabetic subjects and several T1D patients. Both the IFN-γ and the IL-10 responses were greater in non-diabetic individuals who carried at least one non T1D-risk DQ allele. These results indicate that in non-diabetic individuals, the presence of a diabetes protective or neutral HLA-DQ molecule may lead to a regulatory T cell response to insulin, whereas in T1D individuals, this ability may be muted or absent. Other studies using cytokine ELISPOT assays with epitopes from beta cell specific self-antigens, proinsulin, and insulinoma-associated antigen 2 (IA-2) provide similar results with a proinflammatory response in disease and regulatory response in health [37][38].
    Recently, researchers identified both pro- and anti-inflammatory cytokine T cell responses to hybrid insulin peptides (HIPs) from longitudinal peripheral blood samples of individuals genetically at risk for T1D who either developed islet autoantibodies or remained seronegative [39]. HIPs are neoantigens that form in the lysozymes of beta cells via a covalent bond between a fragment of C-peptide and another peptide from a beta cell protein [40]. In this manner, autoreactive T cells that are specific for HIPs may escape into the periphery because these neoantigens are not presented in the thymus during T cell education. In this entry, individuals who became autoantibody positive or who progressed to clinical T1D (high blood sugars requiring exogenous insulin treatment) had a predominantly proinflammatory response to the HIPs, and these responses correlated to worsening measurements of blood glucose control. Separate studies have also found T cell responses to HIPs in newly diagnosed T1D patients [41][42][43].
    As islet antigen-specific Tregs are present within healthy individuals, these cells have been cloned after culture with IA-2 (IA-2709–736) or proinsulin peptides (B:11–30, B:9–28) [44]. Interestingly, although the cells produced IL-10 in response to the islet antigen and were able to suppress the proliferation of T cells, the study found that direct cell-to-cell contact was required for the suppression to occur. The autoantigen-specific Tregs were further able to express cytotoxic molecules (i.e., granzyme A and granzyme B) and directly kill islet autoantigen-loaded antigen-presenting cells in a perforin/granzyme-dependent manner. These results indicate that antigen-specific Tregs are potent regulators of pathogenic T cells as well as antigen presenting cells in healthy individuals.
    The age of T1D onset may also help direct T cell responses to beta cell proteins, as Ueno et al. measured CD4 T cell responses to glutamic acid decarboxylase (GAD), preproinsulin, and IGRP in adult-onset versus childhood-onset T1D patients [45]. In adult patients, there was predominantly a Th1 response to IGRP, whereas those with childhood onset had a Th2 immune response with Tr1 regulatory cells. In fact, the frequency of Tr1 cells responding to IGRP in adult-onset patients was much lower than in childhood-onset patients and non-diabetic controls. These results indicate that distinct subsets of CD4 T cells may respond to IGRP differently and could influence the timing of disease onset.
    Taken together, these studies indicate that during T1D disease development, there are anti-inflammatory responses to islet autoantigens; however, there is either a defect in that response or the proinflammatory immune response predominates. This concept is highlighted by data from a spontaneous animal model of autoimmune diabetes in which there are regulatory T cells within the inflamed pancreatic islets that are directed against an immunodominant peptide, insulin B:9–23, but insulitis and diabetes still develop [46]. At the current time, it is unknown and under investigation whether islet antigen-specific Tregs are present in human insulitis.

    5. Structural Basis of a Treg T Cell Receptor Recognizing Peptide/MHC

    To better understand the structural basis of a proinsulin-specific Treg, Rossjohn et al. solved the crystal structure of a Treg T cell receptor (TCR) binding to proinsulin/DR4 and compared this to the canonical TCR docking pattern for a proinsulin-specific effector T cell [47]. Proinsulin-specific Tregs were cloned and then induced to become iTregs via interaction with tolerogenic dendritic cells. Typically, the α chain of the TCR docks over the β chain of the MHC class II molecule, while the β chain of the TCR docks over the MHCα. However, this Treg crystal structure determined that the TCRα chain overlaid the MHCα chain, while the TCRβ chain overlaid the β chain of the proinsulin/DR4 complex. Thus, a possible structural mechanism exists with reversed polarity docking of the TCR that may account for the difference in response when Tregs recognize a self-antigen versus effector T cells for the same peptide/MHC complex. Although the study identified a novel docking motif for proinsulin-specific Tregs in the context of DR4, it is unknown whether this unusual docking motif extends to other Treg cell specificities at this time.
    In a separate study, two murine CD8 T cell receptors specific for a nucleoprotein epitope (NP366) presented by the MHC class I molecule, H-2Db, docked with a 180 degree position relative to other CD8 TCR-peptide-MHC class I complexes [48]. Although not a Treg TCR–peptide–MHC class II interaction, the authors found that the responses were defective in downstream signal transduction and proliferative capacity. Therefore, irregular docking of a TCR on a peptide–MHC complex may play an important role in how T cells respond to various peptides, including self-peptides.

    References

    1. Coppieters, K.T.; Dotta, F.; Amirian, N.; Campbell, P.D.; Kay, T.W.H.; Atkinson, M.A.; Roep, B.O.; von Herrath, M.G. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J. Exp. Med. 2012, 209, 51–60.
    2. Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965, 14, 619–633.
    3. Campbell-Thompson, M.; Fu, A.; Kaddis, J.S.; Wasserfall, C.; Schatz, D.A.; Pugliese, A.; Atkinson, M.A. Insulitis and β-Cell Mass in the Natural History of Type 1 Diabetes. Diabetes 2016, 65, 719–731.
    4. Arif, S.; Leete, P.; Nguyen, V.; Marks, K.; Nor, N.M.; Estorninho, M.; Kronenberg-Versteeg, D.; Bingley, P.J.; Todd, J.A.; Guy, C.; et al. Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 2014, 63, 3835–3845.
    5. Leete, P.; Willcox, A.; Krogvold, L.; Dahl-Jørgensen, K.; Foulis, A.K.; Richardson, S.J.; Morgan, N.G. Differential Insulitic Profiles Determine the Extent of β-Cell Destruction and the Age at Onset of Type 1 Diabetes. Diabetes 2016, 65, 1362–1369.
    6. Hinman, R.M.; Cambier, J.C. Role of B lymphocytes in the pathogenesis of type 1 diabetes. Curr. Diab. Rep. 2014, 14, 543.
    7. Mayer-Davis, E.J.; Lawrence, J.M.; Dabelea, D.; Divers, J.; Isom, S.; Dolan, L.; Imperatore, G.; Linder, B.; Marcovina, S.; Pettitt, D.J.; et al. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002–2012. N. Engl. J. Med. 2017, 376, 1419–1429.
    8. Insel, R.A.; Dunne, J.L.; Atkinson, M.A.; Chiang, J.L.; Dabelea, D.; Gottlieb, P.A.; Greenbaum, C.J.; Herold, K.C.; Krischer, J.P.; Lernmark, Å.; et al. Staging presymptomatic type 1 diabetes: A scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015, 38, 1964–1974.
    9. Ziegler, A.G.; Rewers, M.; Simell, O.; Simell, T.; Lempainen, J.; Steck, A.; Winkler, C.; Ilonen, J.; Veijola, R.; Knip, M.; et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013, 309, 2473–2479.
    10. Simmons, K.M.; Michels, A.W. Type 1 diabetes: A predictable disease. World J. Diabetes 2015, 6, 380–390.
    11. Herold, K.C.; Bundy, B.N.; Long, S.A.; Bluestone, J.A.; DiMeglio, L.A.; Dufort, M.J.; Gitelman, S.E.; Gottlieb, P.A.; Krischer, J.P.; Linsley, P.S.; et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N. Engl. J. Med. 2019, 381, 603–613.
    12. Tisch, R.; McDevitt, H. Insulin-dependent diabetes mellitus. Cell 1996, 85, 291–297.
    13. Wicker, L.S.; Miller, B.J.; Fischer, P.A.; Pressey, A.; Peterson, L.B. Genetic control of diabetes and insulitis in the nonobese diabetic mouse. Pedigree analysis of a diabetic H-2nod/b heterozygote. J. Immunol. 1989, 142, 781–784.
    14. Wicker, L.S.; Appel, M.C.; Dotta, F.; Pressey, A.; Miller, B.J.; DeLarato, N.H.; Fischer, P.A.; Boltz, R.C.; Peterson, L.B. Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes. J. Exp. Med. 1992, 176, 67–77.
    15. Schmidt, D.; Verdaguer, J.; Averill, N.; Santamaria, P. A mechanism for the major histocompatibility complex-linked resistance to autoimmunity. J. Exp. Med. 1997, 186, 1059–1075.
    16. Lühder, F.; Katz, J.; Benoist, C.; Mathis, D. Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities. J. Exp. Med. 1998, 187, 379–387.
    17. Tsai, S.; Serra, P.; Clemente-Casares, X.; Yamanouchi, J.; Thiessen, S.; Slattery, R.M.; Elliott, J.F.; Santamaria, P. Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 2013, 110, 3471–3476.
    18. Barrett, J.C.; Clayton, D.G.; Concannon, P.; Akolkar, B.; Cooper, J.D.; Erlich, H.A.; Julier, C.; Morahan, G.; Nerup, J.; Nierras, C.; et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 2009, 41, 703–707.
    19. Hu, X.; Deutsch, A.J.; Lenz, T.L.; Onengut-Gumuscu, S.; Han, B.; Chen, W.M.; Howson, J.M.M.; Todd, J.A.; De Bakker, P.I.W.; Rich, S.S.; et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 2015, 47, 898–905.
    20. Robertson, C.C.; Inshaw, J.R.J.; Onengut-Gumuscu, S.; Chen, W.-M.; Santa Cruz, D.F.; Yang, H.; Cutler, A.J.; Crouch, D.J.M.; Farber, E.; Bridges, S.L.; et al. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes. Nat. Genet. 2021, 53, 962–971.
    21. Dendrou, C.A.; Petersen, J.; Rossjohn, J.; Fugger, L. HLA variation and disease. Nat. Rev. Immunol. 2018, 18, 325–339.
    22. Erlich, H.; Valdes, A.M.; Noble, J.; Carlson, J.A.; Varney, M.; Concannon, P.; Mychaleckyj, J.C.; Todd, J.A.; Bonella, P.; Fear, A.L.; et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: Analysis of the type 1 diabetes genetics consortium families. Diabetes 2008, 57, 1084–1092.
    23. Pugliese, A.; Boulware, D.; Yu, L.; Babu, S.; Steck, A.K.; Becker, D.; Rodriguez, H.; Di Meglio, L.; Evans-Molina, C.; Harrison, L.C.; et al. HLA-DRB1∗15:01-DQA1∗01:02-DQB1∗06:02 haplotype protects autoantibody-positive relatives from type 1 diabetes throughout the stages of disease progression. Diabetes 2016, 65, 1109–1119.
    24. Simmons, K.M.; Mitchell, A.M.; Alkanani, A.A.; McDaniel, K.A.; Baschal, E.E.; Armstrong, T.; Pyle, L.; Yu, L.; Michels, A.W. Failed Genetic Protection: Type 1 Diabetes in the Presence of HLA-DQB1*06:02. Diabetes 2020, 69, 1763–1769.
    25. Nakayama, M.; Simmons, K.M.; Michels, A.W. Molecular Interactions Governing Autoantigen Presentation in Type 1 Diabetes. Curr. Diab. Rep. 2015, 15, 113.
    26. Grazia Roncarolo, M.; Gregori, S.; Battaglia, M.; Bacchetta, R.; Fleischhauer, K.; Levings, M.K. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 2006, 212, 28–50.
    27. Groux, H.; O’Garra, A.; Bigler, M.; Rouleau, M.; Antonenko, S.; de Vries, J.E.; Roncarolo, M.G. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997, 389, 737–742.
    28. Grossman, W.J.; Verbsky, J.W.; Tollefsen, B.L.; Kemper, C.; Atkinson, J.P.; Ley, T.J. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 2004, 104, 2840–2848.
    29. Solé, P.; Santamaria, P. Re-Programming Autoreactive T Cells Into T-Regulatory Type 1 Cells for the Treatment of Autoimmunity. Front. Immunol. 2021, 12, 684240.
    30. Lindley, S.; Dayan, C.M.; Bishop, A.; Roep, B.O.; Peakman, M.; Tree, T.I.M. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005, 54, 92–99.
    31. Brusko, T.M.; Wasserfall, C.H.; Clare-Salzler, M.J.; Schatz, D.A.; Atkinson, M.A. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 2005, 54, 1407–1414.
    32. Haseda, F.; Imagawa, A.; Murase-Mishiba, Y.; Terasaki, J.; Hanafusa, T. CD4+ CD45RA− FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes. Clin. Exp. Immunol. 2013, 173, 207–216.
    33. Hull, C.M.; Peakman, M.; Tree, T.I.M. Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it? Diabetologia 2017, 60, 1839–1850.
    34. Danke, N.A.; Koelle, D.M.; Yee, C.; Beheray, S.; Kwok, W.W. Autoreactive T Cells in Healthy Individuals. J. Immunol. 2004, 172, 5967–5972.
    35. Yang, J.; Danke, N.A.; Berger, D.; Reichstetter, S.; Reijonen, H.; Greenbaum, C.; Pihoker, C.; James, E.A.; Kwok, W.W. Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein-Reactive CD4 + T Cells in Human Subjects. J. Immunol. 2006, 176, 2781–2789.
    36. Nakayama, M.; McDaniel, K.; Fitzgerald-Miller, L.; Kiekhaefer, C.; Snell-Bergeon, J.K.; Davidson, H.W.; Rewers, M.; Yu, L.; Gottlieb, P.; Kappler, J.W.; et al. Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects. Proc. Natl. Acad. Sci. USA 2015, 112, 4429–4434.
    37. Arif, S.; Tree, T.I.; Astill, T.P.; Tremble, J.M.; Bishop, A.J.; Dayan, C.M.; Roep, B.O.; Peakman, M. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J. Clin. Investig. 2004, 113, 451–463.
    38. Arif, S.; Pujol-Autonell, I.; Kamra, Y.; Williams, E.; Yusuf, N.; Domingo-Vila, C.; Shahrabi, Y.; Pollock, E.; Khatri, L.; Peakman, M.; et al. Mapping T Cell Responses to Native and Neo-Islet Antigen Epitopes in at Risk and Type 1 Diabetes Subjects. Front. Immunol. 2021, 12, 675746.
    39. Mitchell, A.M.; Alkanani, A.A.; McDaniel, K.A.; Pyle, L.; Waugh, K.; Steck, A.K.; Nakayama, M.; Yu, L.; Gottlieb, P.A.; Rewers, M.J.; et al. T-cell responses to hybrid insulin peptides prior to type 1 diabetes development. Proc. Natl. Acad. Sci. USA 2021, 118, e2019129118.
    40. Delong, T.; Wiles, T.A.; Baker, R.L.; Bradley, B.; Barbour, G.; Reisdorph, R.; Armstrong, M.; Powell, R.L.; Reisdorph, N.; Kumar, N.; et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 2016, 351, 711–714.
    41. Baker, R.L.; Rihanek, M.; Hohenstein, A.C.; Nakayama, M.; Michels, A.; Gottlieb, P.A.; Haskins, K.; Delong, T. Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes 2019, 68, 1830–1840.
    42. Arribas-Layton, D.; Guyer, P.; Delong, T.; Dang, M.; Chow, I.-T.; Speake, C.; Greenbaum, C.J.; Kwok, W.W.; Baker, R.L.; Haskins, K.; et al. Hybrid Insulin Peptides are Recognized by Human T Cells in the Context of DRB1*04:01. Diabetes 2020.
    43. Wiles, T.A.; Hohenstein, A.; Landry, L.G.; Dang, M.; Powell, R.; Guyer, P.; James, E.A.; Nakayama, M.; Haskins, K.; Delong, T.; et al. Characterization of Human CD4 T Cells Specific for a C-Peptide/C-Peptide Hybrid Insulin Peptide. Front. Immunol. 2021, 12, 668680.
    44. Tree, T.I.M.; Lawson, J.; Edwards, H.; Skowera, A.; Arif, S.; Roep, B.O.; Peakman, M. Naturally Arising Human CD4 T-Cells That Recognize Islet Autoantigens and Secrete Interleukin-10 Regulate Proinflammatory T-Cell Responses via Linked Suppression. Diabetes 2010, 59, 1451–1460.
    45. Chujo, D.; Nguyen, T.-S.; Foucat, E.; Blankenship, D.; Banchereau, J.; Nepom, G.T.; Chaussabel, D.; Ueno, H. Adult-onset type 1 diabetes patients display decreased IGRP-specific Tr1 cells in blood. Clin. Immunol. 2015, 161, 270–277.
    46. Spence, A.; Purtha, W.; Tam, J.; Dong, S.; Kim, Y.; Ju, C.; Sterling, T.; Nakayama, M.; Robinson, W.H.; Bluestone, J.A.; et al. Revealing the specificity of regulatory T cells in murine autoimmune diabetes. Proc. Natl. Acad. Sci. USA 2018, 115, 5265–5270.
    47. Beringer, D.X.; Kleijwegt, F.S.; Wiede, F.; van der Slik, A.R.; Loh, K.L.; Petersen, J.; Dudek, N.L.; Duinkerken, G.; Laban, S.; Joosten, A.; et al. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. Nat. Immunol. 2015, 16, 1153–1161.
    48. Gras, S.; Chadderton, J.; Del Campo, C.M.; Farenc, C.; Wiede, F.; Josephs, T.M.; Sng, X.Y.X.; Mirams, M.; Watson, K.A.; Tiganis, T.; et al. Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune Response. Immunity 2016, 45, 749–760.
    More
    Information
    Subjects: Immunology
    Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
    View Times: 134
    Revisions: 4 times (View History)
    Update Date: 25 Mar 2022
    Table of Contents
      1000/1000

      Confirm

      Are you sure you want to delete?

      Video Upload Options

      Do you have a full video?
      Cite
      If you have any further questions, please contact Encyclopedia Editorial Office.
      Mitchell, A.M. Regulatory T Cells in Type 1 Diabetes. Encyclopedia. Available online: https://encyclopedia.pub/entry/20946 (accessed on 07 February 2023).
      Mitchell AM. Regulatory T Cells in Type 1 Diabetes. Encyclopedia. Available at: https://encyclopedia.pub/entry/20946. Accessed February 07, 2023.
      Mitchell, Angela M. "Regulatory T Cells in Type 1 Diabetes," Encyclopedia, https://encyclopedia.pub/entry/20946 (accessed February 07, 2023).
      Mitchell, A.M. (2022, March 23). Regulatory T Cells in Type 1 Diabetes. In Encyclopedia. https://encyclopedia.pub/entry/20946
      Mitchell, Angela M. ''Regulatory T Cells in Type 1 Diabetes.'' Encyclopedia. Web. 23 March, 2022.
      Top
      Feedback