Research ArticleImmunology

A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands

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Science Signaling  02 Feb 2021:
Vol. 14, Issue 668, eabc4479
DOI: 10.1126/scisignal.abc4479

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Stronger responses to weak ligands

The protein tyrosine kinase ZAP70 links activated T cell antigen receptors (TCRs) to downstream signaling pathways. Because of its critical role in activating immune responses, ZAP70 is normally in an autoinhibited state unless there is sufficiently prolonged stimulation of the TCR to induce phosphorylation of ZAP70. Shen et al. used mouse models to characterize the effect of a disease-associated R360P mutation in ZAP70. This mutation disrupted the autoinhibition of ZAP70, leading to enhanced responses to weak or self-ligands. These results reinforce the importance of ZAP70 autoinhibition for preventing autoimmune diseases.


The cytoplasmic kinase ZAP70 is critical for T cell antigen receptor (TCR) signaling. The R360P mutation in ZAP70 is responsible for an early-onset familial autoimmune syndrome. The structural location and biochemical signaling effects of the R360P mutation are consistent with weakening of the autoinhibitory conformation of ZAP70. Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling. In addition, the R360P mutation resulted in enhanced follicular helper T cell expansion after LCMV infection. To eliminate the possibility of a TCR repertoire shift, the OTI transgenic TCR was introduced into R360P mice, which resulted in enhanced T cell responses to weaker stimuli, including weak agonists and a self-peptide. These observations suggest that disruption of ZAP70 autoinhibition by the R360P mutation enables increased mature T cell sensitivity to self-antigens that would normally be ignored by wild-type T cells, a mechanism that may contribute to the break of tolerance in human patients with R360P mutation.

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