Autoreactive CD4+ T cells are involved in the pathogenesis of many autoimmune diseases, but the antigens that stimulate their responses have been difficult to identify and in most cases are not well defined. In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have identified the peptide WE14 from chromogranin A (ChgA) as the antigen for highly diabetogenic CD4+ T cell clones. Peptide truncation and extension analysis shows that WE14 bound to the NOD mouse major histocompatibility complex class II molecule I-Ag7 in an atypical manner, occupying only the carboxy-terminal half of the I-Ag7 peptide-binding groove. This finding extends the list of T cell antigens in type 1 diabetes and supports the idea that autoreactive T cells respond to unusually presented self peptides.
At a glance
- Pancreatic islet-specific T-cell clones from nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 86, 8000–8004 (1989). , , , &
- Pathogenic T-cell clones in autoimmune diabetes: more lessons from the NOD mouse. Adv. Immunol. 87, 123–162 (2005).
- Islet-specific T-cell clones from the NOD mouse respond to β-granule antigen. Diabetes 43, 197–203 (1994). &
- Biochemical characterization of a beta cell membrane fraction antigenic for autoreactive T cell clones. J. Autoimmun. 14, 343–351 (2000). , &
- The first external domain of the nonobese diabetic mouse class II I-A β chain is unique. Proc. Natl. Acad. Sci. USA 84, 2435–2439 (1987). &
- Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science 237, 286–289 (1987). , , &
- Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249, 1433–1436 (1990). &
- Following a diabetogenic T cell from genesis through pathogenesis. Cell 74, 1089–1100 (1993). , , , &
- T-cell receptor transgenic response to an endogenous polymorphic autoantigen determines susceptibility to diabetes. Diabetes 53, 978–988 (2004). et al.
- On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes 57, 1321–1330 (2008). et al.
- Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence, that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice. J. Immunol. 166, 908–917 (2001). et al.
- Evidence for shared recognition of a peptide ligand by a diverse panel of non-obese diabetic mice-derived, islet-specific, diabetogenic T cell clones. Int. Immunol. 14, 1439–1447 (2002). et al.
- WE-14, a chromogranin a-derived neuropeptide. Ann. NY Acad. Sci. 971, 311–316 (2002). et al.
- NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. Diabetes 40, 842–849 (1991). , &
- Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J. Clin. Invest. 115, 1942–1952 (2005). et al.
- The importance of chromogranin A in the development and function of endocrine pancreas. Regul. Pept. 151, 19–25 (2008). , , , &
- Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur. J. Immunol. 25, 1056–1062 (1995). , , &
- Mimotopes for alloreactive and conventional T cells in a peptide-MHC display library. PLoS Biol. 2, 523–533 (2004). , , , &
- Use of baculovirus MHC/peptide display libraries to characterize T-cell receptor ligands. Immunol. Rev. 210, 156–170 (2006). et al.
- A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288, 505–511 (2000). et al.
- Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. Immunity 12, 699–710 (2000). et al.
- Occurrence of WE-14 and chromogranin A-derived peptides in tissues of the human and bovine gastro-entero-pancreatic system and in human neuroendocrine neoplasia. J. Endocrinol. 151, 409–420 (1996). , , &
- Chromogranin A and its derived peptides in the rat and porcine gastro-entero-pancreatic system. Expression, localization, and characterization. Adv. Exp. Med. Biol. 482, 205–213 (2000). et al.
- T cell receptor recognition of MHC class II-bound peptide flanking residues enhances immunogenicity and results in altered TCR V region usage. Immunity 7, 387–399 (1997). , , &
- The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues. J. Immunol. 169, 739–749 (2002). et al.
- The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J. Immunol. 178, 6051–6057 (2007). , , &
- Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity 22, 81–92 (2005). et al.
- Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immunodominant epitope of MBP complexed with I-Au . Immunity 17, 83–94 (2002). et al.
- Colocalization of WE-14 immunostaining with the classical islet hormones in the porcine pancreas. Adv. Exp. Med. Biol. 426, 139–144 (1997). , , &
- Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J. Immunol. 171, 538–541 (2003). et al.
- HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J. Clin. Invest. 116, 2226–2236 (2006). et al.
- The role of HLA-DQ8 β 57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456, 534–538 (2008). et al.
- Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 56, 3541–3553 (2007). et al.
- Tissue transglutaminase and the stress response. Amino Acids 33, 385–394 (2007). , &
- Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine-induced destruction. J. Immunol. 175, 1248–1256 (2005). et al.
- Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002). et al.
- Isolation and primary structure of a novel chromogranin A-derived peptide, WE-14, from a human midgut carcinoid tumour. FEBS Lett. 301, 319–321 (1992). , , , &
- Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity. J. Clin. Invest. 115, 2268–2276 (2005). , , &
- In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat. Protocols 1, 2856–2860 (2006). , , , &
- Two better cell lines for making hybridomas expressing specific T cell receptors. J. Immunol. 143, 1822–1825 (1989). et al.
- Antigen-specific, T region-restricted interactions in vitro between tumor cell lines and T cell hybridomas. J. Immunol. 128, 2164–2169 (1982). , , , &
- Production of soluble MHC class II proteins with covalently bound single peptides. Nature 369, 151–154 (1994). , , , &
- Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity 8, 675–682 (1998). , , , &
- Binding of a soluble αβ T-cell receptor to superantigen/major histocompatibility complex ligands. Proc. Natl. Acad. Sci. USA 91, 8462–8466 (1994). , , , &