Title: Quantitative Reduction of the TCR Adapter Protein SLP-76 Unbalances Immunity and Immune Regulation
Authors: Siggs, Owen M
Miosge, Lisa A
Daley, Stephen R
Asquith, Kelly
Foster, Paul S
Liston, Adrian
Goodnow, Christopher C # ×
Issue Date: Mar-2015
Publisher: American Association of Immunologists
Series Title: Journal of Immunology vol:194 issue:6 pages:2587-95
Article number: 1400326
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.
ISSN: 0022-1767
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Genetics of Autoimmunity
× corresponding author
# (joint) last author

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