Lsh, an SNF2/helicase family member, is required for proliferation of mature T lymphocytes

Lsh (Hells) is closely related to SNF2/helicase family members that remodel chromatin and thus regulate gene transcription. In the adult mouse Lsh is expressed primarily in lymphoid tissue, showing the highest level in thymoc ytes, Lsh gene expression can be induced in thymic pro-T cells by pre-T cel l receptor crosslinking and in mature T cells by T cell receptor crosslinki ng together with costimulation via CD28, The time course of Lsh gene and pr otein expression correlated closely with the onset of S phase of the cell c ycle. To explore the function of Lsh during lymphoid development or activat ion, we deleted the Lsh gene by homologous recombination in ES cells. Fetal liver cells from Lsh(-/-) were used as a source of hematopoietic precursor s to reconstitute lymphoid development in Rag2(-/-) mice. Lsh-/- (compared to Lsh+/+ or +/-) chimeras showed a modest reduction in thymocyte numbers d ue to a partial arrest at the transition from the CD4(-)CD8(-) stage to the CD4(+)CD8(+) stage of T cell development. Mature peripheral lymphocytes we re reduced in number to approximate to 60% for T cells and 40% for B cells; however, V(D)J recombination of the immune receptor genes was normal. Alth ough polyclonal activation of Lsh-/- T cells induced normal levels of cytok ines, cell proliferation was severely suppressed and cells underwent apopto sis, Several genes involved in the regulation of apoptosis were expressed n ormally with the exception of Bcl-2 that was actually elevated. These findi ngs demonstrate that Lsh is not obligatory for normal lymphoid development but is essential for normal proliferation of peripheral T lymphocytes.