Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome
Anastasia Nijnik, Sara Dawson, Tanya L. Crockford, Lisa Woodbine, Supawan Visetnoi, Sophia Bennett, Margaret Jones, Gareth D. Turner, Penelope A. Jeggo, Christopher C. Goodnow, Richard J. Cornall
Anastasia Nijnik, Sara Dawson, Tanya L. Crockford, Lisa Woodbine, Supawan Visetnoi, Sophia Bennett, Margaret Jones, Gareth D. Turner, Penelope A. Jeggo, Christopher C. Goodnow, Richard J. Cornall
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Research Article Immunology

Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome

Abstract

Hypomorphic mutations in DNA ligase IV (LIG4) cause a human syndrome of immunodeficiency, radiosensitivity, and growth retardation due to defective DNA repair by the nonhomologous end-joining (NHEJ) pathway. Lig4-null mice are embryonic lethal, and better mouse models are needed to study human LigIV syndrome. We recently identified a viable mouse strain with a Y288C hypomorphic mutation in the Lig4 gene. Lig4Y288C mice exhibit a greater than 10-fold reduction of LigIV activity in vivo and recapitulate the immunodeficiency and growth retardation seen in human patients. Here, we have demonstrated that the Lig4Y288C mutation leads to multiple defects in lymphocyte development and function, including impaired V(D)J recombination, peripheral lymphocyte survival and proliferation, and B cell class switch recombination. We also highlight a high incidence of thymic tumors in the Lig4Y288C mice, suggesting that wild-type LigIV protects against malignant transformation. These findings provide explanations for the complex lymphoid phenotype of human LigIV syndrome.

Authors

Anastasia Nijnik, Sara Dawson, Tanya L. Crockford, Lisa Woodbine, Supawan Visetnoi, Sophia Bennett, Margaret Jones, Gareth D. Turner, Penelope A. Jeggo, Christopher C. Goodnow, Richard J. Cornall

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Figure 1

Partial arrest in lymphocyte development in Lig4Y288C strain.

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Partial arrest in lymphocyte development in Lig4Y288C strain. (A) Fl...
(A) Flow cytometry profiles of the thymus of WT, Rag1–/–, and Lig4Y288C mice stained for CD4, CD8, CD44, and CD25 and gated on total thymocytes (upper panels) or CD4–CD8– double-negative thymocytes (lower panels). Numbers represent the percentages of cells in the plot that fall within the different regions, corresponding to different stages of thymocyte differentiation. (B) Absolute number of CD4–CD8– double-negative (DN), CD4+CD8+ double-positive (DP), and CD4 and CD8 single-positive cells in the thymus of WT, Rag1–/–, and Lig4Y288C mice. Bars represent mean ± 95% CI; n ≥ 6. (C) Flow cytometry of the bone marrow of WT, Rag1–/–, and Lig4Y288C mice stained for B220, IgM, IgD (upper panels), or for B220 and CD43 (lower panels) and gated on B220+ cells or total lymphocytes, respectively. Numbers represent the percentages of cells in the plot that fall within the different regions, corresponding to different stages of B cell differentiation. (D) Absolute numbers of B220+CD43+ pro–B, B220+CD25+ pre–B, and B220+IgM+IgD– immature B cells in the bone marrow of WT, Rag1–/–, and Lig4Y288C (1 tibia and femur). Bars represent mean ± 95% CI; n ≥ 5.