Characterization of the dominant autoreactive T-cell epitope in spontaneous autoimmune haemolytic anaemia of the NZB mouse

C. R. Shen, Frank James Ward, A. Devine, J. A. Luross, P. A. Lowrey, D. C. Wraith, C. J. Elson, Robert Norman Barker

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

NZB mice spontaneously develop autoimmune haemolytic anaemia (AIHA) due to a T help er-dependent autoantibody response against the erythrocyte anion channel protein, Band 3. Here, we characterize the recognition of the Band 3 sequence 861-874, which carries the dominant, I-E-d-restricted T cell epitope. The ability of N and C-terminal truncated versions of peptide 861-874 to elicit NZB splenic T-cell proliferation indicated that the core epitope spans residues 862-870. Next, a set of alanine substitution analogues was tested to determine which residues functioned either as MHC anchor or TCR contact residues. A combination of proliferation and MHC:peptide binding assays identified residues 862(L), 864(V), 865(L), and 869(K) as I-E-d anchor residues, and 868(V) as the only TCR contact residue. The ability of the wild-type sequence 861-874 to compete with a high affinity reference peptide for binding to I-E-d indicates that the escape of pathogenic NZB T cells from purging of the autoreactive repertoire cannot be attributed to ineffective presentation of peptide 861-874 by its restricting element. It will now be possible to design altered peptide ligands of Band 3 861-874, in order to further dissect the mechanisms responsible for the maintenance and loss of T cell tolerance to RBC autoantigens, and to modulate the immune response in AIHA. (C) 2002 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)149-157
Number of pages8
JournalJournal of Autoimmunity
Volume18
Issue number2
DOIs
Publication statusPublished - 2002

Keywords

  • auto-reactive T cells
  • epitope
  • NZB mouse
  • autoimmune haemolytic anaemia
  • Band 3
  • CLASS-II MOLECULES
  • PEPTIDE BINDING
  • ENCEPHALOMYELITIS
  • MHC
  • ANTIGEN
  • MICE
  • AUTOANTIBODIES
  • REPERTOIRE
  • TOLERANCE
  • RECEPTOR

Cite this

Characterization of the dominant autoreactive T-cell epitope in spontaneous autoimmune haemolytic anaemia of the NZB mouse. / Shen, C. R.; Ward, Frank James; Devine, A.; Luross, J. A.; Lowrey, P. A.; Wraith, D. C.; Elson, C. J.; Barker, Robert Norman.

In: Journal of Autoimmunity, Vol. 18, No. 2, 2002, p. 149-157.

Research output: Contribution to journalArticle

Shen, C. R. ; Ward, Frank James ; Devine, A. ; Luross, J. A. ; Lowrey, P. A. ; Wraith, D. C. ; Elson, C. J. ; Barker, Robert Norman. / Characterization of the dominant autoreactive T-cell epitope in spontaneous autoimmune haemolytic anaemia of the NZB mouse. In: Journal of Autoimmunity. 2002 ; Vol. 18, No. 2. pp. 149-157.
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AU - Barker, Robert Norman

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AB - NZB mice spontaneously develop autoimmune haemolytic anaemia (AIHA) due to a T help er-dependent autoantibody response against the erythrocyte anion channel protein, Band 3. Here, we characterize the recognition of the Band 3 sequence 861-874, which carries the dominant, I-E-d-restricted T cell epitope. The ability of N and C-terminal truncated versions of peptide 861-874 to elicit NZB splenic T-cell proliferation indicated that the core epitope spans residues 862-870. Next, a set of alanine substitution analogues was tested to determine which residues functioned either as MHC anchor or TCR contact residues. A combination of proliferation and MHC:peptide binding assays identified residues 862(L), 864(V), 865(L), and 869(K) as I-E-d anchor residues, and 868(V) as the only TCR contact residue. The ability of the wild-type sequence 861-874 to compete with a high affinity reference peptide for binding to I-E-d indicates that the escape of pathogenic NZB T cells from purging of the autoreactive repertoire cannot be attributed to ineffective presentation of peptide 861-874 by its restricting element. It will now be possible to design altered peptide ligands of Band 3 861-874, in order to further dissect the mechanisms responsible for the maintenance and loss of T cell tolerance to RBC autoantigens, and to modulate the immune response in AIHA. (C) 2002 Elsevier Science Ltd.

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