Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness.
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.
Department of Medicine, Rosalind Russell and Ephraim Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143.|Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
Lih-Yun
LY
Hsu
Department of Medicine, Rosalind Russell and Ephraim Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143.|Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
Debra A
0000-0001-6215-2964
DA
Cheng
Department of Medicine, Rosalind Russell and Ephraim Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143.|Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
Yiling
Y
Chen
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
Hong-Erh
HE
Liang
Department of Medicine, Rosalind Russell and Ephraim Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143 aweiss@medicine.ucsf.edu.|Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
Arthur
0000-0002-2414-9024
A
Weiss
D000818:Animals; D017209:Apoptosis; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis / Q000502:physiology; D011487:Protein Conformation; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D015854:Up-Regulation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry / Q000502:physiology*
D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse