The Bloom's syndrome helicase is critical for development and function of the alphabeta T-cell lineage.
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 beta-selection checkpoint that was partially p53 dependent. Blm-deficient thymocytes rearranged their T-cell receptor (TCR) beta 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.
Babbe
Holger
H
Department of Microbiology, Columbia University Medical Center, 701 W. 168th St., New York, NY 10032, USA. bvr2101@columbia.edu
Chester
Nicholas
N
Leder
Philip
P
Reizis
Boris
B
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D019070:Cell Lineage; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053484:RecQ Helicases; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology
D016693:Receptors, Antigen, T-Cell, alpha-beta; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases