PMID- 18093540
OWN - NLM
STAT- MEDLINE
DCOM- 20080205
LR  - 20211020
IS  - 1074-7613 (Print)
IS  - 1097-4180 (Electronic)
IS  - 1074-7613 (Linking)
VI  - 27
IP  - 6
DP  - 2007 Dec
TI  - Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance 
      differentially titrate in response to nucleotide substitutions.
PG  - 912-26
AB  - 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.
FAU - Siggs, Owen M
AU  - Siggs OM
AD  - John Curtin School of Medical Research and Australian Phenomics Facility, The 
      Australian National University, Canberra 2601, Australia.
FAU - Miosge, Lisa A
AU  - Miosge LA
FAU - Yates, Adele L
AU  - Yates AL
FAU - Kucharska, Edyta M
AU  - Kucharska EM
FAU - Sheahan, Daniel
AU  - Sheahan D
FAU - Brdicka, Tomas
AU  - Brdicka T
FAU - Weiss, Arthur
AU  - Weiss A
FAU - Liston, Adrian
AU  - Liston A
FAU - Goodnow, Christopher C
AU  - Goodnow CC
LA  - eng
GR  - R01 AI052127/AI/NIAID NIH HHS/United States
GR  - R01 AI052127-05/AI/NIAID NIH HHS/United States
GR  - U19 AI100627/AI/NIAID NIH HHS/United States
GR  - R01 AI52127/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Immunity
JT  - Immunity
JID - 9432918
RN  - 0 (Autoantibodies)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Autoantibodies/biosynthesis
MH  - *Immune Tolerance
MH  - *Immunity
MH  - Immunoglobulin E/biosynthesis
MH  - Immunoglobulin G/biosynthesis
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Receptors, Antigen, T-Cell/physiology
MH  - Signal Transduction
MH  - Structure-Activity Relationship
MH  - T-Lymphocytes, Helper-Inducer/classification
MH  - ZAP-70 Protein-Tyrosine Kinase/genetics/*physiology
PMC - PMC3163119
MID - NIHMS36634
COIS- Competing Interests Statement The authors declare that they have no competing 
      financial interests.
EDAT- 2007/12/21 09:00
MHDA- 2008/02/06 09:00
PMCR- 2011/08/28
CRDT- 2007/12/21 09:00
PHST- 2007/06/27 00:00 [received]
PHST- 2007/09/05 00:00 [revised]
PHST- 2007/11/02 00:00 [accepted]
PHST- 2007/12/21 09:00 [pubmed]
PHST- 2008/02/06 09:00 [medline]
PHST- 2007/12/21 09:00 [entrez]
PHST- 2011/08/28 00:00 [pmc-release]
AID - S1074-7613(07)00548-1 [pii]
AID - 10.1016/j.immuni.2007.11.013 [doi]
PST - ppublish
SO  - Immunity. 2007 Dec;27(6):912-26. doi: 10.1016/j.immuni.2007.11.013.