Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility

Author:

Dong Tobias X1ORCID,Othy Shivashankar1ORCID,Greenberg Milton L1,Jairaman Amit1,Akunwafo Chijioke1,Leverrier Sabrina1,Yu Ying1,Parker Ian12,Dynes Joseph L1,Cahalan Michael D13ORCID

Affiliation:

1. Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States

2. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States

3. Institute for Immunology, University of California, Irvine, Irvine, United States

Abstract

Ca2+ influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here, we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+ along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+ signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+ transients: short-duration ‘sparkles’ and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance.

Funder

National Institutes of Health

National Science Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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