title: Quantitative reduction of the TCR adapter protein SLP-76 unbalances immunity and immune regulation.
abstract: Gene variants that disrupt TCR signaling can cause severe immune deficiency, yet less disruptive variants are sometimes associated with immune pathology. Null mutations of the gene encoding the scaffold protein Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76), for example, cause an arrest of T cell positive selection, whereas a synthetic membrane-targeted allele allows limited positive selection but is associated with proinflammatory cytokine production and autoantibodies. Whether these and other enigmatic outcomes are due to a biochemical uncoupling of tolerogenic signaling, or simply a quantitative reduction of protein activity, remains to be determined. In this study we describe a splice variant of Lcp2 that reduced the amount of wild-type SLP-76 protein by ~90%, disrupting immunogenic and tolerogenic pathways to different degrees. Mutant mice produced excessive amounts of proinflammatory cytokines, autoantibodies, and IgE, revealing that simple quantitative reductions of SLP-76 were sufficient to trigger immune dysregulation. This allele reveals a dose-sensitive threshold for SLP-76 in the balance of immunity and immune dysregulation, a common disturbance of atypical clinical immune deficiencies.
authors: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; owen.siggs@sanger.ac.uk chris.goodnow@anu.edu.au.
authors: Owen M
authors: OM
authors: Siggs
authors: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia;
authors: Lisa A
authors: LA
authors: Miosge
authors: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia;
authors: Stephen R
authors: SR
authors: Daley
authors: Priority Research Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales 2300, Australia; and.
authors: Kelly
authors: K
authors: Asquith
authors: Priority Research Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales 2300, Australia; and.
authors: Paul S
authors: PS
authors: Foster
authors: Department of Microbiology and Immunology, Flanders Institute for Biotechnology and University of Leuven, Leuven 3000, Belgium.
authors: Adrian
authors: A
authors: Liston
authors: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia; owen.siggs@sanger.ac.uk chris.goodnow@anu.edu.au.
authors: Christopher C
authors: CC
authors: Goodnow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007109:Immunity / Q000235:genetics / Q000276:immunology*; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000974:Antibodies, Antinuclear; D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D007073:Immunoglobulin E