Fig. 7: Schematic overview of the multiple effects of TGF-β on negative selection.

In the absence of TGF-β signaling, highly autoreactive thymocytes escape cortical negative selection (1). They then acquire CXCR3 at their surface and a large fraction of them are trapped at the CMJ (cortico-medullary junction) (2), preventing their entrance in the medulla where a second wave of negative selection occurs. The few highly autoreactive thymocytes entering the medulla fail to condition mTECs for an efficient negative selection: AIRE^pos mTEC differentiation is largely altered as well as their ability to express TRA (3). Highly autoreactive thymocytes escape the second wave of negative selection (4). In sum, in the absence of TGF-β signaling control in thymocytes, several mechanisms essential for elimination of highly autoreactive thymocytes are impaired in the thymus allowing them to reach the periphery where they can induce tissue damage. The figure has been created by J.C.M.