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J Immunol. 2019 Apr 26. pii: ji1801033. doi: 10.4049/jimmunol.1801033. [Epub ahead of print]

Cutting Edge: ATM Influences Germinal Center Integrity.

Author information

1
Immunology Program, Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
2
Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065.
3
Institute for Cancer Genetics, Department of Pediatrics, Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032; and.
4
Department of Biology, City College of New York, City University of New York, New York, NY 10031.
5
Immunology Program, Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065; chaudhuj@mskcc.org.

Abstract

The DNA damage response protein ATM has long been known to influence class switch recombination in ex vivo-cultured B cells. However, an assessment of B cell-intrinsic requirement of ATM in humoral responses in vivo was confounded by the fact that its germline deletion affects T cell function, and B:T cell interactions are critical for in vivo immune responses. In this study, we demonstrate that B cell-specific deletion of ATM in mice leads to reduction in germinal center (GC) frequency and size in response to immunization. We find that loss of ATM induces apoptosis of GC B cells, likely due to unresolved DNA lesions in cells attempting to undergo class-switch recombination. Accordingly, suboptimal GC responses in ATM-deficient animals are characterized by decreased titers of class-switched Abs and decreased rates of somatic hypermutation. These results unmask the critical B cell-intrinsic role of ATM in maintaining an optimal GC response following immunization.

PMID:
31028119
DOI:
10.4049/jimmunol.1801033

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