Breaking T cell tolerance with foreign and self co-immunogens

A study of autoimmune B and T cell epitopes of cytochrome c

Mark J. Mamula, Rong Hwa Lin, Charles A. Janeway, John A. Hardin

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

The initiation of autoimmune B cell and T cell responses by self Ag or by foreign pathogens (molecular mimics) is not well understood. In the present study, cytochrome c (cyt c) was used as a model autoantigen to investigate how self-proteins are involved in the priming of autoimmune T cell responses. Immunization with foreign cyt c has been extensively analyzed in previous studies as a model for both humoral and cellular immune responses. Mice do not, however, make antibody or T cell responses to immunization with self (mouse) cyt c. In addition, T cell tolerance can be broken by autoreactive B cells that are readily elicited by immunization with cross-reactive foreign cyt c. These immune B cells presumably bind self cyt c and process and present the self Ag to stimulate an autoreactive T cell response. Autoreactive T cell clones derived by this mechanism are all specific for determinants within amino acids 1-80 of the cyt c protein presented by I-Ek. No T cell responses were observed to the carboxyl terminal 81-104 fragment that dominates the response to foreign cyt c. All clones derived in this study are stimulated by a polypeptide encompassing amino acids 54-68 and utilized the Vβ 8.2 TCR gene. In contrast, T cells stimulated by foreign cyt c did indeed respond to fragment 81-104 and appear to utilize alternate TCR genes. Our data demonstrate that B cells specific for linear determinants distributed along the entire length of the foreign cyt c molecule can provide the stimulus required for breaking T cell tolerance to self cyt c. The applications of this work to understanding the mechanisms of autoimmune disease are discussed.

Original languageEnglish (US)
Pages (from-to)789-795
Number of pages7
JournalJournal of Immunology
Volume149
Issue number3
StatePublished - Aug 1 1992
Externally publishedYes

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B-Lymphocyte Epitopes
T-Lymphocyte Epitopes
Cytochromes c
T-Lymphocytes
B-Lymphocytes
Immunization
Clone Cells
Cytochromes c1
Amino Acids
Humoral Immunity
Cellular Immunity
Genes
Autoimmune Diseases
Proteins
Peptides

ASJC Scopus subject areas

  • Immunology

Cite this

Breaking T cell tolerance with foreign and self co-immunogens : A study of autoimmune B and T cell epitopes of cytochrome c. / Mamula, Mark J.; Lin, Rong Hwa; Janeway, Charles A.; Hardin, John A.

In: Journal of Immunology, Vol. 149, No. 3, 01.08.1992, p. 789-795.

Research output: Contribution to journalArticle

Mamula, Mark J. ; Lin, Rong Hwa ; Janeway, Charles A. ; Hardin, John A. / Breaking T cell tolerance with foreign and self co-immunogens : A study of autoimmune B and T cell epitopes of cytochrome c. In: Journal of Immunology. 1992 ; Vol. 149, No. 3. pp. 789-795.
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abstract = "The initiation of autoimmune B cell and T cell responses by self Ag or by foreign pathogens (molecular mimics) is not well understood. In the present study, cytochrome c (cyt c) was used as a model autoantigen to investigate how self-proteins are involved in the priming of autoimmune T cell responses. Immunization with foreign cyt c has been extensively analyzed in previous studies as a model for both humoral and cellular immune responses. Mice do not, however, make antibody or T cell responses to immunization with self (mouse) cyt c. In addition, T cell tolerance can be broken by autoreactive B cells that are readily elicited by immunization with cross-reactive foreign cyt c. These immune B cells presumably bind self cyt c and process and present the self Ag to stimulate an autoreactive T cell response. Autoreactive T cell clones derived by this mechanism are all specific for determinants within amino acids 1-80 of the cyt c protein presented by I-Ek. No T cell responses were observed to the carboxyl terminal 81-104 fragment that dominates the response to foreign cyt c. All clones derived in this study are stimulated by a polypeptide encompassing amino acids 54-68 and utilized the Vβ 8.2 TCR gene. In contrast, T cells stimulated by foreign cyt c did indeed respond to fragment 81-104 and appear to utilize alternate TCR genes. Our data demonstrate that B cells specific for linear determinants distributed along the entire length of the foreign cyt c molecule can provide the stimulus required for breaking T cell tolerance to self cyt c. The applications of this work to understanding the mechanisms of autoimmune disease are discussed.",
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