Promiscuous gene expression and central T-cell tolerance: more than meets the eye

Self-tolerance of the T-cell repertoire is mediated by multiple mechanisms operating both in the thymus (‘central tolerance’) and in peripheral lymphoid and non-lymphoid organs (‘peripheral tolerance’). Based on the recent finding that tissue-specific genes are commonly expressed in the thymus, this strict delineation has been blurred. Medullary thymic epithelial cells have been identified as a unique cell type that expresses a wide range of tissue-specific genes in a ‘promiscuous’ manner and displays these self-antigens for intrathymic repertoire selection. The array of promiscuously expressed genes appears random rather than the result of specific selection. The gains and pitfalls of this tolerance mechanism have important implications for autoimmunity.