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 4

T and B cell development in MM mice is inhibited at receptor gene rearrangement stages.

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T and B cell development in MM mice is inhibited at receptor gene rearra...
(A) Spectratypes of VhJ558 and VhQ52 family genes were performed using splenocytes from MM mice and C57BL/10 controls. Representative data are shown. (B) The number of cells in the MM mouse lymph nodes (inguinal, axillaries, cervical, and mesenteric; P < 0.001), thymus (Thy; P = 0.005), and spleen (Spl; P < 0.001) than in those of wild-type mice. Results are mean and SD of 5–6 mice (6–9 weeks old). (C and D) CD4+ and CD8+ T cells were sorted from spleens and lymph nodes of MM and control mice and stimulated by 10 μg/ml (C, top) and indicated concentrations of anti-CD3 and anti-CD28 (D). MTT assay showed less T cell proliferation in MM than in wild-type cells (stimulated CD4+, P = 0.002; stimulated CD8+, P < 0.001; CD4+ and CD8+ at all concentrations, P < 0.001). (C, bottom) B220+CD19+ B cells were sorted from spleens of MM and control mice and stimulated by indicated concentrations of LPS. MTT assay showed more B cell proliferation in MM than in wild-type cells stimulated with 0 μg/ml LPS (P < 0.001) or 0.1 μg/ml LPS (P = 0.001). #P < 0.01, †P < 0.001 versus wild type.