There are many regulatory and inductive influences on the generation and propagation of response to a self-antigen such as myelin basic protein (MBP). The form of the antigen, the nature of the antigen-presenting cell, the level of tolerance in the T cell repertoire under scrutiny, and members of antigen-based and T cell receptor (TCR)-based regulatory circuits are all directly involved. Aspects of these influences on the expressed T cell repertoire to MBP and at points, to another neuronal protein, proteolipid protein (=PLP), will be studied. A regulatory circuit comprised of a CD4+ T regulatory cell (a suppressor-induced cell) and a CD8+ T suppressor cell has been described in our laboratory, which acts to control the activity of the CD4+ effector T cells responsible for disease. In this proposal, one of the aims will be to study the role of the CD8+ T cell in this circuit--its specificity and regulatory target. TCR transgenic systems will be employed with low frequencies of T cells bearing the transgenic receptor. Likewise, regulation can be initiated by antigen, and although it also proceeds to engage the TCR idiopeptide-based circuit, we would like to study the T suppressor cell induced by suppressor T cell-inducing determinants on MBP. We will investigate the relationship between the form in which the antigenic determinant exists and the V gene usage in the TCR of the selected T cells. Two types of tolerance experiments will be undertaken. One of them has as its focus the subdominant and cryptic determinants on the self protein, MBP, and their importance in perpetuating the neurologic disease, experimental allergic encephalomyelitis. Further, the effectiveness of peptides in inducing tolerance during chronic phases of disease will be tested. We will explore how a change in the affinity of peptide ligands for the MHC molecule can affect the direction of T cell maturation and influence the proportion of Th1 of Th2 cells produced after antigenic stimulation. These studies should help to establish a clearer understanding and potential therapies for this autoimmune disease.
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