Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

Kent, Sally C.; Mannering, Stuart I.; Michels, Aaron; Babon, Jenny Aurielle B.

doi:10.1007/s11892-017-0915-y

Cited by 32 publications

(27 citation statements)

References 99 publications

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“…Here, we show that CD4 + T cells specific for proinsulin C-peptide can be detected in the peripheral blood of individuals with recent-onset T1D. This concurs with the detection of C-peptide-specific CD4 + T cells in the islets of the small number of organ donors with T1D who have been studied (16)(17)(18)23). C-peptide-specific CD4 + T cell clones isolated from peripheral blood recognized epitopes from throughout the C-peptide with many in its C-terminal half.…”

Section: Discussionsupporting

confidence: 86%

“…that many islet-infiltrating CD4 + T cell clones are restricted by HLA-DQ2/DQ8 (16)(17)(18)23). Broadly, there is overlap between the HLA-DQ2 and HLA-DQ8 restricted clones isolated from islets and peripheral blood (SI Appendix, Table S6) (16,17), although fine mapping reveals that very few are identical.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, others have identified similar HLA-DQ8 restricted, islet-derived, T cell receptors (17). Although the numbers of donors are still small at this time, 10 of the 12 proinsulin-specific clones analyzed to date recognize epitopes derived from C-peptide (18).…”

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confidence: 99%

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Proinsulin C-peptide is an autoantigen in people with type 1 diabetes

Elso

Tresoldi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4+ T cells recognize C-peptide–derived epitopes, we hypothesized that full-length C-peptide (PI33–63), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4+ T cells in people with T1D. CD4+ T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide–specific CD4+ T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide–specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8trans, or HLA-DQ2trans, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4+ T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4+ T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Proinsulin C-peptide is an autoantigen in people with type 1 diabetes

Elso

Tresoldi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…This large and collaborative consortium has provided the frame work to study the human pancreas, islets embedded within the pancreas, pancreatic lymph nodes, and spleen in those with and without disease. Many insights have been gleaned from a decade of studies and recently reviewed ( 48 , 49 ).…”

Section: Network For Pancreatic Organ Donors (Npod)mentioning

confidence: 99%

Determining Antigen Specificity of Human Islet Infiltrating T Cells in Type 1 Diabetes

Nakayama

Michels

2019

Front. Immunol.

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Type 1 diabetes, the immune mediated form of diabetes, represents a prototypical organ specific autoimmune disease in that insulin producing pancreatic islets are specifically targeted by T cells. The disease is now predictable in humans with the measurement of type 1 diabetes associated autoantibodies (islet autoantibodies) in the peripheral blood which are directed against insulin and beta cell proteins. With an increasing incidence of disease, especially in young children, large well-controlled clinical prevention trials using antigen specific immunotherapy have been completed but with limited clinical benefit. To improve outcomes, it is critical to understand the antigen and T cell receptor repertoires of those cells that infiltrate the target organ, pancreatic islets, in human type 1 diabetes. With international networks to identify organ donors with type 1 diabetes, improved immunosequencing platforms, and the ability to reconstitute T cell receptors of interest into immortalized cell lines allows antigen discovery efforts for rare tissue specific T cells. Here we review the disease pathogenesis of type 1 diabetes with a focus on human islet infiltrating T cell antigen discovery efforts, which provides necessary knowledge to define biomarkers of disease activity and improve antigen specific immunotherapy approaches for disease prevention.

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“…The stark contrast in risk highlights the importance of DQ8 in T1D development and DQ6 in providing dominant protection. Furthermore, DQ8 has been shown to present peptides of (pro)insulin to activate CD4 T cells isolated from the remaining islets of recent-onset T1D organ donors, implicating DQ8 responding T cells in T1D pathogenesis (21)(22)(23)(24). The evidence that DQ8 is (1) common in T1D, (2) confers significant genetic risk, and (3) is involved in disease pathogenesis, makes the DQ8 molecule an attractive therapeutic target to treat the underlying autoimmunity in T1D.…”

Section: Hla-dq8 As a Molecular Target In Type 1 Diabetesmentioning

confidence: 99%

Rationally designed small molecules to prevent type 1 diabetes

Ostrov

Gottlieb

Michels

2019

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review: To review the recent findings that small 'drug-like' compounds block disease-specific HLA molecules in type 1 diabetes (T1D). Recent findings: The predominant genetic risk for developing T1D, the immune mediated form of diabetes, is conferred through human leukocyte antigen (HLA) genes. One such gene, termed HLA-DQ8, is present in 50-60% of patients with T1D and those at-risk. DQ8 presents diseaserelevant peptides to T cells, which mediate tissue specific destruction of pancreatic islets. Using a structure-based approach to evaluate the 'druggability' of the DQ8 molecule, methyldopa, a clinically well-established oral anti-hypertensive agent, was discovered to bind DQ8. Methyldopa blocked the activation of DQ8 specific T cells responding to self-antigens such as insulin but not influenza. In a proof-of-concept clinical trial (NCT01883804), methyldopa was administered to recent-onset T1D patients with the DQ8 gene that confirmed the mechanism of action and diminished inflammatory T cell responses towards insulin. Summary: Methyldopa blocks the diabetes-specific function of HLA-DQ8, which represents a personalized medicine approach to treat the underlying autoimmunity in T1D. Clinical trials are warranted and underway to evaluate methyldopa in potentially preserving residual beta-cell function in those with new-onset and at-risk for T1D.

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Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

Cited by 32 publications

References 99 publications

Proinsulin C-peptide is an autoantigen in people with type 1 diabetes

Proinsulin C-peptide is an autoantigen in people with type 1 diabetes

Determining Antigen Specificity of Human Islet Infiltrating T Cells in Type 1 Diabetes

Rationally designed small molecules to prevent type 1 diabetes

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