The Mechanisms of T Cell Selection in the Thymus

Autoreactive T cells are negatively selected in the medulla through mTEC expression of self-antigens such as tissue-restricted antigens (TRAs). TRAs are promiscuously expressed under the control of the autoimmune regulator Aire, but also regulated by the transcription factor Fezf2 in mTECs. Fezf2 is essential for the suppression of autoimmune responses even in Aire-expressing animals, as the antigens targeted by Fezf2 and Aire only partially overlap. T cells undergo positive and negative selection in the thymic cortex and medulla, respectively. A promiscuous expression of a wide array of self-antigens in the thymus is essential for the negative selection of self-reactive T cells and the establishment of central tolerance. Aire was originally thought to be the exclusive factor regulating the expression of tissue-restricted antigens, but Fezf2 recently emerged as a critical transcription factor in this regulatory activity. Fezf2 is selectively expressed in thymic medullary epithelial cells, regulates a large number of tissue-restricted antigens and suppresses the onset of autoimmune responses. Here, we discuss novel findings on the transcriptional mechanisms of tissue restricted-antigen expression in the medullary thymic epithelial cells and its effects on T cell selection. T cells undergo positive and negative selection in the thymic cortex and medulla, respectively. A promiscuous expression of a wide array of self-antigens in the thymus is essential for the negative selection of self-reactive T cells and the establishment of central tolerance. Aire was originally thought to be the exclusive factor regulating the expression of tissue-restricted antigens, but Fezf2 recently emerged as a critical transcription factor in this regulatory activity. Fezf2 is selectively expressed in thymic medullary epithelial cells, regulates a large number of tissue-restricted antigens and suppresses the onset of autoimmune responses. Here, we discuss novel findings on the transcriptional mechanisms of tissue restricted-antigen expression in the medullary thymic epithelial cells and its effects on T cell selection.