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Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions.

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 pleiotropic functions of ZAP-70 and their differential response to graded variation provide a paradigm for understanding the complex outcomes of human genetic variation.

journal_name

Immunity

journal_title

Immunity

authors

Siggs OM,Miosge LA,Yates AL,Kucharska EM,Sheahan D,Brdicka T,Weiss A,Liston A,Goodnow CC

doi

10.1016/j.immuni.2007.11.013

subject

Has Abstract

pub_date

2007-12-01 00:00:00

pages

912-26

issue

6

eissn

1074-7613

issn

1097-4180

pii

S1074-7613(07)00548-1

journal_volume

27

pub_type

杂志文章

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