Immunity
Volume 27, Issue 6, 21 December 2007, Pages 912-926
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Article
Opposing Functions of the T Cell Receptor Kinase ZAP-70 in Immunity and Tolerance Differentially Titrate in Response to Nucleotide Substitutions

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Summary

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.

MOLIMMUNO

Cited by (0)

3

These authors contributed equally to this work.

4

Present address: Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

5

Present address: Food Standards Australia New Zealand, Barton ACT 2600, Australia.

6

Present address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic.

7

Present address: Department of Immunology, University of Washington, Seattle, WA 98195, USA.