Shifting T‐cell activation thresholds in autoimmunity and determinant spreading

Summary: The best‐characterized autoimmune T‐cell response is that to myelin basic protein (MBP), MBP has classically been regarded as a sequestered antigen that does not cause negative selection. This view has been fostered by the observation that T‐cell receptor‐transgenic T cells that are specific for the “immunodominant determinant” on the molecule, MBP:Ac 1–11, persist as naive cells in MBP‐expressing H‐Z” mice. The same T cells, however, can cause autoimmune pathology once they have been primed by environmental stimulation to become memory cells. Once the autoimmune response to Ac1‐11 has been engaged, determinant spreading occurs and second‐wave T‐cell responses that are specific for weaker, “cryptic” determinants like MBP: 121–140 develop. Although the nature of these cryptic determinants has been enigmatic, recent studies using MBP‐”‐mice have provided new insights. These studies showed that MBP is not a sequestered antigen, but one that causes negative selection; as MBP: 121–140 is actually the immunodominant determinant in MBP‐/‐ mice, it tolerizes high avidity clones in MBP+/+ mice, making it appear cryptic. Based on this new information, we attempt here to redefine the MBP‐specific repertoire within the theoretical framework of the threshold model for negative selection, and we propose a model of shifting T‐cell activation thresholds to explain how ignorant/naive T cells can become effector cells of autoimmune pathology and why this effector cell repertoire spreads.