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N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes.

Jin N, Wang Y, Crawford F, White J, Marrack P, Dai S, Kappler JW
Proc Natl Acad Sci U S A 112 13318-23 (2015)
Cited: 31 times
EuropePMC logo PMID: 26453556

Abstract

Chromogranin A (ChgA) is an autoantigen for CD4(+) T cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). The natural ChgA-processed peptide, WE14, is a weak agonist for the prototypical T cell, BDC-2.5, and other ChgA-specific T-cell clones. Mimotope peptides with much higher activity share a C-terminal motif, WXRM(D/E), that is predicted to lie in the p5 to p9 position in the mouse MHC class II, IA(g7) binding groove. This motif is also present in WE14 (WSRMD), but at its N terminus. Therefore, to place the WE14 motif into the same position as seen in the mimotopes, we added the amino acids RLGL to its N terminus. Like the other mimotopes, RLGL-WE14, is much more potent than WE14 in T-cell stimulation and activates a diverse population of CD4(+) T cells, which also respond to WE14 as well as islets from WT, but not ChgA(-/-) mice. The crystal structure of the IA(g7)-RLGL-WE14 complex confirmed the predicted placement of the peptide within the IA(g7) groove. Fluorescent IA(g7)-RLGL-WE14 tetramers bind to ChgA-specific T-cell clones and easily detect ChgA-specific T cells in the pancreas and pancreatic lymph nodes of NOD mice. The prediction that many different N-terminal amino acid extensions to the WXRM(D/E) motif are sufficient to greatly improve T-cell stimulation leads us to propose that such a posttranslational modification may occur uniquely in the pancreas or pancreatic lymph nodes, perhaps via the mechanism of transpeptidation. This modification could account for the escape of these T cells from thymic negative selection.

Articles - 5dmk mentioned but not cited (2)

  1. N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes. Jin N, Wang Y, Crawford F, White J, Marrack P, Dai S, Kappler JW. Proc Natl Acad Sci U S A 112 13318-13323 (2015)
  2. Structural plasticity in I-Ag7 links autoreactivity to hybrid insulin peptides in type I diabetes. Erausquin E, Serra P, Parras D, Santamaria P, López-Sagaseta J. Front Immunol 13 924311 (2022)


Reviews citing this publication (17)

  1. Next-generation regulatory T cell therapy. Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Nat Rev Drug Discov 18 749-769 (2019)
  2. Environmental risk factors for type 1 diabetes. Rewers M, Ludvigsson J. Lancet 387 2340-2348 (2016)
  3. HLA variation and disease. Dendrou CA, Petersen J, Rossjohn J, Fugger L. Nat. Rev. Immunol. 18 325-339 (2018)
  4. Class II MHC antigen processing in immune tolerance and inflammation. Jurewicz MM, Stern LJ. Immunogenetics 71 171-187 (2019)
  5. T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Burrack AL, Martinov T, Fife BT. Front Endocrinol (Lausanne) 8 343 (2017)
  6. Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity. Bandyopadhyay GK, Mahata SK. Front Endocrinol (Lausanne) 8 20 (2017)
  7. Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders. Weissert R. Front Immunol 8 336 (2017)
  8. Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation. Tarbell KV, Egen JG. J. Leukoc. Biol. (2018)
  9. The Challenges of Identifying Environmental Determinants of Type 1 Diabetes: In Search of the Holy Grail. Butalia S, Kaplan GG, Khokhar B, Haubrich S, Rabi DM. Diabetes Metab Syndr Obes 13 4885-4895 (2020)
  10. Know thy immune self and non-self: Proteomics informs on the expanse of self and non-self, and how and where they arise. Joyce S, Ternette N. Proteomics 21 e2000143 (2021)
  11. Hidden in Plain View: Discovery of Chimeric Diabetogenic CD4 T Cell Neo-Epitopes. Reed BK, Kappler JW. Front Immunol 12 669986 (2021)
  12. T1D Autoantibodies: room for improvement? Yu L, Zhao Z, Steck AK. Curr Opin Endocrinol Diabetes Obes 24 285-291 (2017)
  13. Catestatin as a Target for Treatment of Inflammatory Diseases. Muntjewerff EM, Dunkel G, Nicolasen MJT, Mahata SK, van den Bogaart G. Front Immunol 9 2199 (2018)
  14. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Mahata SK, Corti A. Ann. N. Y. Acad. Sci. 1455 34-58 (2019)
  15. Non-mutational neoantigens in disease. Stern LJ, Clement C, Galluzzi L, Santambrogio L. Nat Immunol 25 29-40 (2024)
  16. Role and function of granin proteins in diabetes mellitus. Herold Z, Doleschall M, Somogyi A. World J Diabetes 12 1081-1092 (2021)
  17. Using mass spectrometry to identify neoantigens in autoimmune diseases: The type 1 diabetes example. Lichti CF, Wan X. Semin Immunol 66 101730 (2023)

Articles citing this publication (12)

  1. Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation. Reed B, Crawford F, Hill RC, Jin N, White J, Krovi SH, Marrack P, Hansen K, Kappler JW. J Exp Med 218 e20192135 (2021)
  2. Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes. Spanier JA, Sahli NL, Wilson JC, Martinov T, Dileepan T, Burrack AL, Finger EB, Blazar BR, Michels AW, Moran A, Jenkins MK, Fife BT. Diabetes 66 3051-3060 (2017)
  3. A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes. Postigo-Fernandez J, Creusot RJ. J Autoimmun 98 13-23 (2019)
  4. Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance. Dastagir SR, Postigo-Fernandez J, Xu C, Stoeckle JH, Firdessa-Fite R, Creusot RJ. Mol Ther Methods Clin Dev 4 27-38 (2017)
  5. A Novel Tolerogenic Antibody Targeting Disulfide-Modified Autoantigen Effectively Prevents Type 1 Diabetes in NOD Mice. Li W, Zhang Y, Li R, Wang Y, Chen L, Dai S. Front Immunol 13 877022 (2022)
  6. A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells. Kobayashi S, Thelin MA, Parrish HL, Deshpande NR, Lee MS, Karimzadeh A, Niewczas MA, Serwold T, Kuhns MS. Proc Natl Acad Sci U S A 117 28950-28959 (2020)
  7. C-terminal modification of the insulin B:11-23 peptide creates superagonists in mouse and human type 1 diabetes. Wang Y, Sosinowski T, Novikov A, Crawford F, Neau DB, Yang J, Kwok WW, Marrack P, Kappler JW, Dai S. Proc. Natl. Acad. Sci. U.S.A. 115 162-167 (2018)
  8. Calcitonin gene-related peptide is a potential autoantigen for CD4 T cells in type 1 diabetes. Li W, Li R, Wang Y, Zhang Y, Tomar MS, Dai S. Front Immunol 13 951281 (2022)
  9. Epitope-based precision immunotherapy of Type 1 diabetes. Firdessa Fite R, Bechi Genzano C, Mallone R, Creusot RJ. Hum Vaccin Immunother 19 2154098 (2023)
  10. How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes. Wang Y, Sosinowski T, Novikov A, Crawford F, White J, Jin N, Liu Z, Zou J, Neau D, Davidson HW, Nakayama M, Kwok WW, Gapin L, Marrack P, Kappler JW, Dai S. Sci Immunol 4 (2019)
  11. Selected Serum Markers Associated with Pathogenesis and Clinical Course of Type 1 Diabetes in Pediatric Patients-The Effect of Disease Duration. Ochocińska A, Wysocka-Mincewicz M, Świderska J, Cukrowska B. J Clin Med 12 2151 (2023)
  12. Stacking the Deck: Studies of Patients with Multiple Autoimmune Diseases Propelled Our Understanding of Type 1 Diabetes as an Autoimmune Disease. Buckner JH, Greenbaum CJ. J. Immunol. 199 3011-3013 (2017)


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