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 6

MM mice have symptoms similar to those of OS patients.

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MM mice have symptoms similar to those of OS patients. (A) The percentag...
(A) The percentage of eosinophils (CCR3highGr-1low), as determined using PBLs of wild-type and MM mice, was greater in MM than in wild-type mice. Results are mean and SD of 12 mice. (B) To examine the skin of wild-type and MM mice, their abdominal hair was shaved. Panel shows the skin color of wild-type and MM mice, typical of more than 10 analyzed. (C–F) Weights of the thymus (C), spleen (D), lymph nodes (E), and liver (F) at the indicated time points were higher in MM than in wild-type mice. Results are mean and SD of more than 50 mice. (G) Vβ usage by CD4+ and CD8+ T cells in 8-week-old wild-type and MM mice was measured by FACS analysis. Results are mean and SD of 5 mice. The percentage of Vβ3+, Vβ4+, Vβ5.1+5.2+, Vβ7+, Vβ10+, Vβ12+, and Vβ13+ CD4+ cells and of Vβ5.1+5.2+, Vβ7+, Vβ10+, Vβ12+, Vβ13+, and Vβ14+ CD8+ cells was lower, while the percentage of Vβ6+, Vβ8.1+8.2+, Vβ8.3+, Vβ9+, and Vβ11+ CD4+ cells and of Vβ6+, Vβ8.1+8.2+, and Vβ11+ CD8+ cells was higher, in MM compared with wild-type mice. (H) Spectratypes of Vα and Vβ family genes were performed using splenocytes from MM mice and C57BL/10 controls. Representative data are shown. *P < 0.05, #P < 0.01, †P < 0.001 versus wild type.