Thymic tolerance as a key brake on autoimmunity

Abstract

Although the thymus has long been recognized as a key organ for T cell selection, the intricate details linking these selection events to human autoimmunity have been challenging to decipher. Over the last two decades, there has been rapid progress in understanding the role of thymic tolerance mechanisms in autoimmunity through genetics. Here we review some of the recent progress in understanding key thymic tolerance processes that are critical for preventing autoimmune disease.

Figure 1.

Properties of mTECs and drivers of TSA-expression. A) Shown is a schematic of a cross section of the thymus. Highlighted are some of the unique and unusual features of mTECs that may help poise them for promoting display of TSA’s and the induction of tolerance. B) Shown is a single representative mTEC and an array of TSA’s being expressed. It now appears that Aire and Fezf2 are unique promoters of TSA expression in mTECs and that there are likely to be other factors beyond this transcriptional pair that drive this process.

Figure 2.

Model of hypomorphic ZAP70 and altered T cell selection. Shown is a theoretical curve for positive selection and negative selection of T cell clones that results in a tolerant repertoire (green shading). In the case of hypomorphic ZAP70 activity the thresholds for both positive and negative selection result in a shift in the repertoire that now includes autoreactive T cell clones (red shading). The regulatory T cell repertoire is likely to fall in the interface between tolerant and autoreactive clones based on the model of induction of Treg fate in moderately self-reactive clones (gray dotted overlay).