The Bloom's Syndrome Helicase Is Critical for Development and Function of the αβ T-Cell Lineage

Abstract

Bloom's syndrome is a genetic disorder characterized by increased incidence of cancer and an immunodeficiency of unknown origin. The BLM gene mutated in Bloom's syndrome encodes a DNA helicase involved in the maintenance of genomic integrity. To explore the role of BLM in the immune system, we ablated murine Blm in the T-cell lineage. In the absence of Blm, thymocytes were severely reduced in numbers and displayed a developmental block at the β-selection checkpoint that was partially p53 dependent. Blm-deficient thymocytes rearranged their T-cell receptor (TCR) β genes normally yet failed to survive and proliferate in response to pre-TCR signaling. Furthermore, peripheral T cells were reduced in numbers, manifested defective homeostatic and TCR-induced proliferation, and produced extensive chromosomal damage. Finally, CD4⁺ and CD8⁺ T-cell responses were impaired upon antigen challenge. Thus, by ensuring genomic stability, Blm serves a vital role for development, maintenance, and function of T lymphocytes, suggesting a basis for the immune deficiency in Bloom's syndrome.

SUPPLEMENTAL MATERIAL

We thank Jennifer McMenamin and Montserrat Michelman for excellent technical help, Chris Wilson for lckCre and CD4Cre mice, and members of the Leder and Rajewsky laboratories for helpful support and discussions.

This work was partially supported by the HHMI.