Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model
Khie Khiong, … , Philippa Marrack, Toshio Hirano
Khie Khiong, … , Philippa Marrack, Toshio Hirano
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1270-1281. https://doi.org/10.1172/JCI30513.
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Research Article

Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model

Abstract

Patients with Omenn syndrome (OS) have hypomorphic RAG mutations and develop varying manifestations of severe combined immunodeficiency. It is not known which symptoms are caused directly by the RAG mutations and which depend on other polymorphic genes. Our current understanding of OS is limited by the lack of an animal model. In the present study, we identified a C57BL/10 mouse with a spontaneous mutation in, and reduced activity of, RAG1. Mice bred from this animal contained high numbers of memory-phenotype T cells and experienced hepatosplenomegaly and eosinophilia, had oligoclonal T cells, and demonstrated elevated levels of IgE, major symptoms of OS. Depletion of CD4+ T cells in the mice caused a reduction in their IgE levels. Hence these “memory mutant” mice are a model for human OS; many symptoms of their disease were direct results of the Rag hypomorphism and some were caused by malfunctions of their CD4+ T cells.

Authors

Khie Khiong, Masaaki Murakami, Chika Kitabayashi, Naoko Ueda, Shin-ichiro Sawa, Akemi Sakamoto, Brian L. Kotzin, Stephen J. Rozzo, Katsuhiko Ishihara, Marileila Verella-Garcia, John Kappler, Philippa Marrack, Toshio Hirano

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Figure 7

Homeostatically proliferating CD4+ T cells express high amounts of Th2 cytokines and are involved in the hyper-IgE status of MM mice.

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Homeostatically proliferating CD4+ T cells express high amounts of Th2 c...
(A and B) CD4+ and CD8+ T cells of the naive phenotype (CD44low) from normal C57BL/10 mice were sorted, labeled with CFSE, and transferred into nonirradiated wild-type and nonirradiated MM 3-day-old (A) and 8-week-old (B) mice. Homeostatic proliferation of CD4+ and CD8+ cells in the spleen and lymph nodes was investigated by FACS analysis and dilution of the CFSE label. Results are mean and SD of 6 mice. This ratio of divided to nondivided cells was higher in MM than in wild-type mice both at 3 days (CD4+, P = 0.02; CD8+, P = 0.03) and at 8 weeks (CD4+, P = 0.01; CD8+, P = 0.02). (C) Intracellular cytokine staining was performed using the CD4+ T cells of 8-week-old wild-type and MM mice and analyzed by FACS. Results are mean and SD of 10 mice. The percentage of cells positive for several cytokines was higher in MM than in wild-type mice (IL-6, P = 0.009; IL-4, P = 0.03). (D) CD4+ T cells of the naive phenotype (CD44low) from normal C57BL/6 SJL (CD45.1+) mice were sorted (99% purity), labeled with CFSE, and transferred into nonirradiated MM mice 8 weeks after birth. Eight days after transfer, CFSE-CD45.1+ cells in the spleen and lymph nodes were investigated by FACS analysis for activation markers CD44 and CD69 and cytokines IL-6 and IL-4. Numbers denote percentage of cells within the ranges indicated by brackets. *P < 0.05, #P < 0.01 versus wild type.