Successful β-selection depends on TCF-1 (HEM4P.228)

Abstract

Abstract The transcription factor TCF-1 is expressed very early during thymic development and is important for early T cell specification. TCF-1 expression further increases after b-selection and is maintained at high levels in differentiated T cells, but its function at these later stages has not been examined. We used mice with conditional alleles of TCF-1 (TCF-1f/f) to delete TCF-1 at two time points of T cell development. Whereas deletion of TCF-1 in double-positive thymocytes (CD4-cre TCF-1f/f) had little impact on later T cell populations, the effect of the deletion at double-negative 3 (DN3) stage (CD2-cre TCF-1f/f) was dramatic. Thymic cellularity of CD2-cre TCF-1f/f mice was decreased more than 10-fold compared to littermates control, and competitive BM chimeras clearly revealed a sharp defect at the b-selection checkpoint in these mice. Analysis of TCF-1-deleted DN3 thymocytes did not reveal any defects in T cell gene expression and pre-TCR expression and signaling. However, post b-selection DN3 and DN4 thymocytes failed to display the increase in cell size and proliferation characteristic of successful b-selection. Because these two phenomena have been previously attributed to c-Myc, we examined its expression and found that c-Myc protein is reduced in TCF-1-deleted post b-selection DN3. We are currently examining the mechanism by which TCF-1 controls c-Myc. Our work to date implicates TCF-1 downstream of the pre-TCR during the development of αβ T cells.