Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions.
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 pleiotropic functions of ZAP-70 and their differential response to graded variation provide a paradigm for understanding the complex outcomes of human genetic variation.
Siggs
Owen M
OM
John Curtin School of Medical Research and Australian Phenomics Facility, The Australian National University, Canberra 2601, Australia.
Miosge
Lisa A
LA
Yates
Adèle L
AL
Kucharska
Edyta M
EM
Sheahan
Daniel
D
Brdicka
Tomas
T
Weiss
Arthur
A
Liston
Adrian
A
Goodnow
Christopher C
CC
D019943:Amino Acid Substitution; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D007108:Immune Tolerance; D007109:Immunity; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000502:physiology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D007073:Immunoglobulin E; D051746:ZAP-70 Protein-Tyrosine Kinase