Cutting Edge: ATM Influences Germinal Center Integrity

• Published in: The Journal of immunology (1950) 2019-06, Vol.202 (11), p.3137-3142
• Main Authors: Nicolas, Laura, Cols, Montserrat, Smolkin, Ryan, Fernandez, Keith C, Yewdell, William T, Yen, Wei-Feng, Zha, Shan, Vuong, Bao Q, Chaudhuri, Jayanta
• Format: Article
• Language: English
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; B-Lymphocytes - physiology; Cells, Cultured; DNA Repair - genetics; Germinal Center - physiology; Immunoglobulin Class Switching; Mice; Mice, Knockout; Receptors, Complement 3d - genetics; Somatic Hypermutation, Immunoglobulin; T-Lymphocytes - physiology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1801033

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.