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Shifting T-cell activation thresholds in autoimmunity and determinant spreading
P V Lehmann1, O S Targoni, T G Forsthuber
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. pvl2@po.cwru.edu
Immunological Reviews
|October 31, 1998
Summary
Myelin basic protein (MBP) is not sequestered but causes T-cell tolerance. In MBP-deficient mice, cryptic determinants become immunodominant, revealing how naive T cells trigger autoimmune disease.
Area of Science:
- Immunology
- Autoimmunity
- T-cell biology
Background:
- Myelin basic protein (MBP) is a key target in autoimmune T-cell responses.
- MBP was traditionally considered a sequestered antigen, not inducing negative selection.
- T-cell receptor-transgenic T cells specific for MBP:Ac1-11 remain naive in MBP-expressing mice but cause disease upon activation.
Purpose of the Study:
- To investigate the role of MBP as a sequestered or non-sequestered antigen.
- To understand the nature of cryptic determinants in MBP-specific autoimmune responses.
- To redefine the MBP-specific T-cell repertoire using the negative selection threshold model.
Main Methods:
- Utilized myelin basic protein knockout (MBP-/-) mice.
- Analyzed T-cell responses to immunodominant and cryptic determinants of MBP.
- Applied the threshold model for negative selection to T-cell activation.
Main Results:
- MBP is not sequestered and actively induces negative selection.
- The determinant MBP:121-140 is immunodominant in MBP-/- mice, tolerizing high-avidity clones in wild-type mice.
- This tolerance makes MBP:121-140 appear cryptic in MBP+/+ mice.
Conclusions:
- MBP functions as a non-sequestered antigen that shapes the T-cell repertoire through negative selection.
- The apparent cryptic nature of certain MBP determinants is due to tolerance induced in wild-type mice.
- A model of shifting T-cell activation thresholds explains the transition of naive T cells to autoimmune effectors and determinant spreading.