Title: Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions
Authors: Siggs, Owen M
Miosge, Lisa A
Yates, Adele L
Kucharska, Edyta M
Sheahan, Daniel
Brdicka, Tomas
Weiss, Arthur
Liston, Adrian ×
Goodnow, Christopher C #
Issue Date: Dec-2007
Publisher: Cell press
Series Title: Immunity vol:27 issue:6 pages:912-926
Abstract: Null mutations that cripple T cell receptor (TCR) signaling explain rare primary immunodeficiencies, but it is not understood why more common polymorphisms that lead to subtle TCR signaling defects are paradoxically associated with autoimmunity. Here we analyzed how a series of Zap70 variants with step-wise decreases in TCR signaling impacted upon opposing TCR functions of immunity and tolerance. One Zap70 variant, murdock, moderately decreased TCR signaling and thymic selection without compromising immunological tolerance, whereas a more severe Zap70 defect, mrtless, abolished thymic-positive selection and led to immunodeficiency. Signaling capacities between these two thresholds disproportionately compromised negative selection and Foxp3(+) regulatory T cell formation, creating a cellular imbalance between immunogenic and tolerogenic functions that resulted in the excessive production of autoantibodies and immunoglobulin E (IgE). The pleictropic functions of ZAP-70 and their differential response to graded variation provide a paradigm for understanding the complex outcomes of human genetic variation.
ISSN: 1074-7613
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Experimental Medicine (-)
Laboratory of Genetics of Autoimmunity
× corresponding author
# (joint) last author

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