Self-antigen expression in thymic epithelial cells in Ifn-γ or Tnf-α deficiency.

ABSTRACT

Insulin expression in the thymic medullary epithelial cells (mTECs) is found to be a critical aspect of maintaining self-tolerance towards that antigen. A lowered insulin expression level in the thymus correlates with susceptibility to Type 1 Diabetes in humans and lead to higher levels of autoreactive T cells in mice. It is therefore, essential to understand the regulatory mechanism of insulin in the mTECs. Previous in vitro studies have shown a negative effect on the expression of insulin in mTECs upon stimulation with the cytokines Ifn-γ and Tnf-α, separately. The objective of this study was to examine the physiological role of these cytokines in vivo. For this purpose, we examined whether these cytokines have a physiological role in regulating thymic insulin expression using the Ifn-γ and Tnf-α knockout models. We found that insulin expression increased in the knockout mice compared to their wild-type counterparts. Aire transcriptional regulator, a known switch for self-antigen expression in the thymus, was also increased in the knockout animals. Four antigens targeted in other autoimmune disorders were also found to have a pattern of increase in the Ifn-γ or Tnf-α knockout models, including one that is known to be Aire-independent in its expression. An increase in mTEC population or thymocyte population was not seen in these knockout mice, revealing a regulatory mechanism that involves cytokine action directly on the transcription of the antigens. These findings suggest regulation of tissue-specific antigen production in the thymus by these two cytokines that is parallel to that controlled by AIRE.