title: Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice.
abstract: Our previous studies have implicated signaling through the tumor necrosis family receptors OX40 and CD30 as critical for maintaining CD4 memory responses. We show that signals through both molecules are also required for CD4 effector-mediated autoimmune tissue damage. Under normal circumstances, male mice deficient in the forkhead transcription factor FoxP3, which lack regulatory CD4 T cells, develop lethal autoimmune disease in the first few weeks of life. However, in the combined absence of OX40 and CD30, FoxP3-deficient mice develop normally and breed successfully. The extensive tissue infiltration and organ destruction characteristic of FoxP3 disease does not appear in these mice, and their mortality is not associated with autoimmunity. Although the absence of OX40 plays the dominant role, FoxP3-deficient mice sufficient in CD30 but deficient in OX40 signals still eventually develop lethal disease. This result was supported by the observation that blocking antibodies to OX40 and CD30 ligands also abrogated disease mediated by FoxP3-deficient T cells. These observations identify OX40 and CD30 signals as essential for the development of clinically relevant CD4-dependent autoimmunity and suggest that combination therapies that abrogate these signals might be used to treat established human autoimmune diseases.
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Birmingham Medical School, Birmingham B15 2TT, England, UK.
authors.forename: Fabrina
authors.initials: F
authors.lastname: Gaspal
authors.forename: David
authors.initials: D
authors.lastname: Withers
authors.forename: Manoj
authors.initials: M
authors.lastname: Saini
authors.forename: Vasileios
authors.initials: V
authors.lastname: Bekiaris
authors.forename: Fiona M
authors.initials: FM
authors.lastname: McConnell
authors.forename: Andrea
authors.initials: A
authors.lastname: White
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.forename: Peter J L
authors.initials: PJ
authors.lastname: Lane
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics; D017730:Ki-1 Antigen / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D015398:Signal Transduction / Q000276:immunology*; D018709:Statistics, Nonparametric
chemical_list: D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D017730:Ki-1 Antigen; C406562:OX40Ig