Expression of TCR Partly Rescues Developmental Arrest and Apoptosis of T cells in Bcl11b/ Mice1

Bcl11b/ mice show developmental arrest at the CD44CD25 double-negative 3 (DN3) or immature CD8single-positive stage of T cell. We have performed detailed analysis of sorted subsets of Bcl11b/ thymocytes, DN3 and CD44CD25 double-negative 4 (DN4) cells. Surface expression of TCR proteins was not detected in DN3 thymocytes and markedly reduced in DN4 thymocytes, whereas expression within the cell was detected in both, suggesting some impairment in processing of TCR proteins from the cytoplasm to the cell surface. This lack of expression, resulting in the absence of pre-TCR signaling, could be responsible for the arrest, but the transgenic TCR or TCR expression on the cell surface failed to promote transition from the DN3 to CD4CD8 double-positive stage of development. This suggests that the pre-TCR signal cannot compensate the deficiency of Bcl11b for development. Bcl11b/ DN3 thymocytes showed normal DNA rearrangements between D and J segments but limited DNA rearrangements between V and DJ without effect of distal or proximal positions. Because this impairment may be due to chromatin accessibility, we have examined histone H3 acetylation in Bcl11b/ DN3 cells using chromatin immuno-precipitation assay. No change was observed in acetylation at the V and D gene locus. Analysis of Bcl11b/ DN4 thymocytes showed apoptosis, accompanied with lower expression of anti-apoptotic proteins, Bcl-xL and Bcl-2, than wild-type DN4 thymo-cytes. Interestingly, the transgenic TCR in those cells reduced apoptosis and raised their protein expression without increased cellularity. These results suggest that Bcl11b deficiency affects many different signaling pathways leading to development arrests. The Journal of Immunology, 2006, 176: 5871–5879