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PanR1, a Dominant Negative Missense Allele of the Gene Encoding TNF- (Tnf), Does Not Impair Lymphoid Development¹

Sophie Rutschmann^*, Kasper Hoebe^*, Jonathan Zalevsky, Xin Du^*, Navjiwan Mann^*, Bassil I. Dahiyat, Paul Steed and Bruce Beutler^2,*

^* Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; and Xencor, Monrovia, CA 91016

A dominant hypomorphic allele of Tnf, PanR1, was identified in a population of G₁ mice born to N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes produced no detectable TNF bioactivity, although normal quantities of immunoreactive TNF were secreted. The phenotype was confined to a critical region on mouse chromosome 17, and then ascribed to a CA transversion at position 3480 of the Tnf gene, corresponding to the amino acid substitution P138T. As a result of subunit exchange, the protein exerts a dominant-negative effect on normal TNF trimers, interfering with the trimer/receptor interaction. Homozygotes are highly susceptible to infection by Listeria monocytogenes, confirming the essential role of TNF in innate immune defense. However, PanR1 mutant mice show normal architecture of the spleen and Peyer’s patches, suggesting that TNF is not essential for the formation of these lymphoid structures.

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