SHIFTING T-CELL ACTIVATION THRESHOLDS IN AUTOIMMUNITY AND DETERMINANTSPREADING

The best-characterized autoimmune T-cell response is that to myelin ba sic protein (MBP). MBP has classically been regarded as a sequestered antigen that does not cause negative selection. This view has been fos tered by the observation that T-cell receptor-transgenic T cells that are specific for the ''immunodominant determinant'' on the molecule, M BP:Ac1-11, persist as naive cells in MBP-expressing H-2(u) mice. The s ame T cells, however, can cause autoimmune pathology once they have be en primed by environmental stimulation to become memory cells. Once th e autoimmune response to Acl-ll has been engaged, determinant spreadin g occurs and second-wave T-cell responses that. are specific for weake r, ''cryptic'' determinants like MBP:121-140 develop. Although the nat ure of these cryptic determinants has been enigmatic, recent studies u sing MBP-/- mice have provided new insights. These studies showed that MBP is not a sequestered antigen, but one that causes negative select ion; as MBP:121-140 is actually the immunodominant determinant in MBP- /- mice, it tolerizes high avidity clones in MBP+/+ mice, making it ap pear cryptic. Based on this new information, we attempt here to redefi ne the MBP-specific repertoire within the theoretical framework of the threshold model for negative selection, and we propose a model of shi fting T-cell activation thresholds to explain how ignorant/naive T cel ls can become effector cells of autoimmune pathology and why this effe ctor cell repertoire spreads.