Modulation of lymphocyte development and function via snail family transcriptional regulators

Antigen receptor-encoding lymphocytes (i.e., B and T cells) are key mediators of the adaptive immune response. Hence, the developmental and functional programs of these cells are crucial to the sustained viability of metazoans such as mouse and man. One strategy to ensure these cellular programs is through the use of tightly orchestrated networks of gene expression. To preserve these networks, a myriad of proteins function to activate or repress particular sets of genes. The Snail family of transcription factors consists of three members: Snai1 (Snail), Snai2 (Slug), and Snai3 (Smuc). These proteins are conserved throughout evolution and share a high degree of protein sequence homology. While best known for roles in developmental biology and malignancy, members of the family (i.e., Snai2) have been shown to function in hematopoietic progenitor biology. Additionally, the overlapping expression of Snail genes is evident in a multitude of hematopoietic cell types. To test whether Snai2 and Snai3 functioned redundantly in hematopoiesis, germline double knockout animals were generated. Analysis of Snai2/Snai3 germline double knockouts demonstrated imbalances in the development of lymphoid and myeloid lineages, which absolutely required the deletion of both Snai2 and Snai3. These animals were iv also affected nonhematopoietically as evidenced by the almost complete absence of female double knockout progeny and accelerated thymic atrophy. Furthermore, one allele of either Snai2 or Snai3 rescued all phenotypes to a similar degree suggesting that both gene products were haplo sufficient in the ability to compensate for the loss of the other three alleles. Snai2/3 conditional double knockout mice were generated in an effort to better ascertain the hematopoietic cell intrinsic roles of Snai2 and Snai3. Snai2/3 conditional double knockout animals expired at approximately one month of age due to rampant autoimmunity inclusive of both IgM and IgG autoantibodies. Adoptive transfer of wildtype regulatory T cells halted autoimmune pathology, autoantibody production, and rescued animals from death. Importantly, autoimmunity was generated in Snai2 sufficient Rag2-/- animals receiving double knockout bone marrow. These data supported a cell intrinsic role for Snai2 and Snai3 in regulating immune tolerance.