T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection
Edited by Jason G. Cyster, University of California, San Francisco, CA, and approved January 19, 2016 (received for review August 25, 2015)
Significance
The control of a microbial infection by effector T cells is intrinsically linked to their migration. However, little is known about the mechanisms that control effector T-cell egress after infection. Sphingosine-1-phosphate receptor-1 (S1PR1) is a G-coupled protein receptor that plays an important role in naive T-cell egress from lymph nodes. However, less is known about its role in regulating effector T-cell trafficking during infection. Here, we used an inducible mouse model with temporally disrupted S1PR1 signaling exclusively in endogenous effector CD8 T cells to demonstrate that, after infection, even in the absence of retention signals such as CC chemokine receptor 7 (CCR7), intrinsic S1PR1 signaling is the overriding factor that regulates effector T-cell egress kinetics from the draining lymph node.
Abstract
Viral clearance requires effector T-cell egress from the draining lymph node (dLN). The mechanisms that regulate the complex process of effector T-cell egress from the dLN after infection are poorly understood. Here, we visualized endogenous pathogen-specific effector T-cell migration within, and from, the dLN. We used an inducible mouse model with a temporally disrupted sphingosine-1-phosphate receptor-1 (S1PR1) gene specifically in endogenous effector T cells. Early after infection, WT and S1PR1−/− effector T cells localized exclusively within the paracortex. This localization in the paracortex by CD8 T cells was followed by intranodal migration by both WT and S1PR1−/− T cells to positions adjacent to both cortical and medullary lymphatic sinuses where the T cells exhibited intense probing behavior. However, in contrast to WT, S1PR1−/− effector T cells failed to enter the sinuses. We demonstrate that, even when LN retention signals such as CC chemokine receptor 7 (CCR7) are down-regulated, T cell intrinsic S1PR1 is the master regulator of effector T-cell emigration from the dLN.
Acknowledgments
We thank Quynh-Mai Pham for assistance in performing experiments and Dr. Evan Jellison in the UConn Health Flow Cytometry Facility. We thank Dr. Tim Hla for critically reading the paper and Dr. Shobha Thangada for her assistance with the study. This work was supported by NIH Grants AI076457 (to B.S.S.), AI097052 (to T.R.M.), AI007387 (to T.T.M.), and AI097375 (to K.M.K.).
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Published online: February 9, 2016
Published in issue: February 23, 2016
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Acknowledgments
We thank Quynh-Mai Pham for assistance in performing experiments and Dr. Evan Jellison in the UConn Health Flow Cytometry Facility. We thank Dr. Tim Hla for critically reading the paper and Dr. Shobha Thangada for her assistance with the study. This work was supported by NIH Grants AI076457 (to B.S.S.), AI097052 (to T.R.M.), AI007387 (to T.T.M.), and AI097375 (to K.M.K.).
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection, Proc. Natl. Acad. Sci. U.S.A.
113 (8) 2182-2187,
https://doi.org/10.1073/pnas.1516485113
(2016).
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