Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants.
We have produced transgenic mice expression hen egg-white lysozyme (HEL) under the control of a ubiquitous promoter, so that in transgenic animals, HEL is presumably present in the serum and thymus throughout the period of establishment of the T-cell repertoire. We show that HEL transgenic H-2d mice with HEL blood levels greater than 10 ng/ml are tolerant to HEL as well as to the immunodominant peptide 108-116. Thus, their T lymphocytes do not proliferate in response to the immunodominant peptide 108-116 after in vivo immunization with HEL or peptide 108-116. In contrast, in transgenic mice tolerant to HEL, the state of tolerance to subdominant peptides 1-18 and 74-96 appears variable and highly depended on HEL blood levels. Complete unresponsiveness is seen when HEL serum levels are high, and this unresponsiveness is reached at a lower HEL concentration for peptide 1-18 than for peptide 74-96. Thus, a hierarchy exists among the three peptides (108-116 much greater than 1-18 greater than 74-96) for induction of a response to HEL and for HEL tolerance induction in T cells specific for these peptides. Persistence in the periphery of autoreactive T cells recognizing subdominant peptides of self-proteins, as shown in this transgenic model, indicates that self-tolerance is limited to a subset of dominant self-peptides and suggests a role for T lymphocytes specific for subdominant determinants in autoimmunity.
U.277 Institut National de la Santé et de la Recherche Médicale, Institut Pasteur, Paris, France.
R
R
Cibotti
J M
JM
Kanellopoulos
J P
JP
Cabaniols
O
O
Halle-Panenko
K
K
Kosmatopoulos
E
E
Sercarz
P
P
Kourilsky
D000818:Animals; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes; D015870:Gene Expression; D006183:H-2 Antigens / Q000276:immunology; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000097:blood / Q000737:chemistry / Q000276:immunology*; D010455:Peptides / Q000276:immunology
D000939:Epitopes; D006183:H-2 Antigens; D010455:Peptides; D009113:Muramidase