Differential requirement of IKK2 for CYLD-dependent representation of thymic and peripheral T-cell populations.

The cylindromatosis tumor suppressor gene (Cyld) encodes an enzyme (CYLD) with deubiquitinating activity that has been implicated in the regulation of thymocyte selection in an NF-κB-essential-modulator (NEMO)-dependent manner. The main known molecular defects in thymocytes with inactive CYLD (LckCre-Cyld(flx9/flx9) ) are the aberrant hyperactivation of NF-κB and JNK pathways. In order to dissect further the molecular mechanism of CYLD-dependent thymocyte selection and address the role of NF-κB specifically, we generated double mutant mice (LckCre-Cyld(flx9/flx9) -Ikk2(flx/flx) ) in which CYLD was inactivated concomitantly with IKK2 (IκB-kinase 2) in thymocytes. Interestingly, thymic development and NF-κB activity in double mutant mice were fully restored, indicating that an IKK2-dependent function of CYLD that leads to the hyperactivation of the NF-κB pathway is primarily responsible for the defective selection of thymocytes. Intriguingly, we observed a greater reduction of CD4(+) and CD8(+) T cells in the periphery of LckCre-Cyld(flx9/flx9) -Ikk2(flx/flx) mice compared with LckCre-Ikk2(flx/flx) mice. Collectively, our data establish CYLD as a critical regulator of thymocyte selection in a manner that depends on IKK2 and NF-κB activation. In addition, our data uncover an IKK2-independent role for CYLD in the establishment of physiological T-cell populations in the periphery.