Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness

Author:

Hsu Lih-Yun12,Cheng Debra A.12ORCID,Chen Yiling12,Liang Hong-Erh2,Weiss Arthur12ORCID

Affiliation:

1. Department of Medicine, Rosalind Russell and Ephraim Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143

2. Howard Hughes Medical Institute, University of California, San Francisco, CA 94143

Abstract

Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-type T cell receptor (TCR) repertoires exhibited relatively normal T cell development. However, crossing the W131A mutant mice to OTII TCR transgenic mice resulted in increased negative selection of OTII+ thymocytes and in increased thymic and peripheral T regulatory cells. Strikingly, increased basal TCR signaling was associated with a marked increase in inhibitory receptor expression and with T cells that were relatively refractory to TCR stimulation. PD-1 inhibitory receptor blockade partially reversed T cell unresponsiveness. Collectively, disruption of normal Zap70 autoinhibition engaged negative feedback mechanisms by which negative selection and inhibitory receptors restrain TCR signaling to enforce both central and peripheral tolerance.

Funder

National Institutes of Health

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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