Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens

Anthony W. Purcell, Weisan Chen, Nicholas J. Ede, Jeffrey J. Gorman, John V. Fecondo, David C. Jackson, Yuming Zhao, James McCluskey

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Abstract

In studying the CTL recognition of peptide determinants derived from the nuclear Ag La (SS-B), we observed significant skewing of the response toward rare components present within the immunogen. Thus, priming of naive mouse lymphocytes in vitro with a synthetic H-2K(b)-binding peptide comprising human La (hLa) residues 51-58 resulted in class I-restricted cytotoxic T cells that failed to recognize naturally presented hLa 51-58 peptide. Instead, the majority of T hybrids recognized a low abundance (≤1%) contaminant present at picomolar concentrations in the original synthesis and identified as a peptide adduct containing N,4-t-butyl asparagine at position 6 of the hLa 51-58 sequence. The preferred T cell recognition of the butyl adduct was not due to increased affinity of this peptide for the H-2K(b) molecule or to the antagonism of CTL recognizing the unmodified determinant. Rather, the bias in the immune response appeared to be the result of partial self-tolerance to the homologous mouse La 51-58 determinant, which differs from its human counterpart by only a single amino acid at position 1 (T→I). Accordingly, the CTL response appeared to be focused on 'non-self' ligands present within the synthesis, even though they were present at very low concentrations. These observations have significant implications for the use of synthetic peptide vaccines, especially those designed to manipulate responses to self peptides such as tumor Ags in which self-tolerance may result in unexpected reactivity.

Original languageEnglish
Pages (from-to)1085-1090
Number of pages6
JournalJournal of Immunology
Volume160
Issue number3
Publication statusPublished - 1 Feb 1998
Externally publishedYes

Cite this

Purcell, A. W., Chen, W., Ede, N. J., Gorman, J. J., Fecondo, J. V., Jackson, D. C., ... McCluskey, J. (1998). Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens. Journal of Immunology, 160(3), 1085-1090.
Purcell, Anthony W. ; Chen, Weisan ; Ede, Nicholas J. ; Gorman, Jeffrey J. ; Fecondo, John V. ; Jackson, David C. ; Zhao, Yuming ; McCluskey, James. / Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens. In: Journal of Immunology. 1998 ; Vol. 160, No. 3. pp. 1085-1090.
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abstract = "In studying the CTL recognition of peptide determinants derived from the nuclear Ag La (SS-B), we observed significant skewing of the response toward rare components present within the immunogen. Thus, priming of naive mouse lymphocytes in vitro with a synthetic H-2K(b)-binding peptide comprising human La (hLa) residues 51-58 resulted in class I-restricted cytotoxic T cells that failed to recognize naturally presented hLa 51-58 peptide. Instead, the majority of T hybrids recognized a low abundance (≤1{\%}) contaminant present at picomolar concentrations in the original synthesis and identified as a peptide adduct containing N,4-t-butyl asparagine at position 6 of the hLa 51-58 sequence. The preferred T cell recognition of the butyl adduct was not due to increased affinity of this peptide for the H-2K(b) molecule or to the antagonism of CTL recognizing the unmodified determinant. Rather, the bias in the immune response appeared to be the result of partial self-tolerance to the homologous mouse La 51-58 determinant, which differs from its human counterpart by only a single amino acid at position 1 (T→I). Accordingly, the CTL response appeared to be focused on 'non-self' ligands present within the synthesis, even though they were present at very low concentrations. These observations have significant implications for the use of synthetic peptide vaccines, especially those designed to manipulate responses to self peptides such as tumor Ags in which self-tolerance may result in unexpected reactivity.",
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Purcell, AW, Chen, W, Ede, NJ, Gorman, JJ, Fecondo, JV, Jackson, DC, Zhao, Y & McCluskey, J 1998, 'Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens', Journal of Immunology, vol. 160, no. 3, pp. 1085-1090.

Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens. / Purcell, Anthony W.; Chen, Weisan; Ede, Nicholas J.; Gorman, Jeffrey J.; Fecondo, John V.; Jackson, David C.; Zhao, Yuming; McCluskey, James.

In: Journal of Immunology, Vol. 160, No. 3, 01.02.1998, p. 1085-1090.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Purcell, Anthony W.

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AB - In studying the CTL recognition of peptide determinants derived from the nuclear Ag La (SS-B), we observed significant skewing of the response toward rare components present within the immunogen. Thus, priming of naive mouse lymphocytes in vitro with a synthetic H-2K(b)-binding peptide comprising human La (hLa) residues 51-58 resulted in class I-restricted cytotoxic T cells that failed to recognize naturally presented hLa 51-58 peptide. Instead, the majority of T hybrids recognized a low abundance (≤1%) contaminant present at picomolar concentrations in the original synthesis and identified as a peptide adduct containing N,4-t-butyl asparagine at position 6 of the hLa 51-58 sequence. The preferred T cell recognition of the butyl adduct was not due to increased affinity of this peptide for the H-2K(b) molecule or to the antagonism of CTL recognizing the unmodified determinant. Rather, the bias in the immune response appeared to be the result of partial self-tolerance to the homologous mouse La 51-58 determinant, which differs from its human counterpart by only a single amino acid at position 1 (T→I). Accordingly, the CTL response appeared to be focused on 'non-self' ligands present within the synthesis, even though they were present at very low concentrations. These observations have significant implications for the use of synthetic peptide vaccines, especially those designed to manipulate responses to self peptides such as tumor Ags in which self-tolerance may result in unexpected reactivity.

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Purcell AW, Chen W, Ede NJ, Gorman JJ, Fecondo JV, Jackson DC et al. Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens. Journal of Immunology. 1998 Feb 1;160(3):1085-1090.