Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants

Area of Science:

• Immunology
• T-cell biology
• Autoimmunity

Background:

• Self-tolerance is crucial for preventing autoimmune diseases.
• The T-cell repertoire develops in the thymus and periphery.
• Understanding the mechanisms of self-tolerance is essential for treating autoimmunity.

Purpose of the Study:

• To investigate the induction of T-cell tolerance to hen egg-white lysozyme (HEL) in transgenic mice.
• To determine the hierarchy of tolerance induction for dominant and subdominant HEL peptides.
• To explore the role of T cells specific for subdominant self-peptides in autoimmunity.

Main Methods:

• Production of transgenic mice expressing hen egg-white lysozyme (HEL) under a ubiquitous promoter.
• Assessment of HEL blood levels in transgenic mice.
• In vivo immunization with HEL and its peptides (108-116, 1-18, 74-96).
• Measurement of T-cell proliferation in response to HEL peptides.

Main Results:

• Transgenic mice with high HEL blood levels (>10 ng/ml) were tolerant to HEL and the immunodominant peptide 108-116.
• Tolerance to subdominant peptides (1-18 and 74-96) was variable and dependent on HEL blood levels.
• A hierarchy of tolerance induction was observed: peptide 108-116 > peptide 1-18 > peptide 74-96.
• Autoreactive T cells specific for subdominant peptides persisted in the periphery.

Conclusions:

• Self-tolerance is primarily established for dominant self-peptides.
• T cells specific for subdominant self-peptides can persist in the periphery, potentially contributing to autoimmunity.
• This transgenic model provides insights into the limitations of self-tolerance and the role of subdominant determinants in autoimmune diseases.