Affiliation:
1. Department of Genetics, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115
2. Department of Microbiology, Columbia University Medical Center, 701 W. 168th St., New York, New York 10032
Abstract
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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
30 articles.
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