T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection

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.n effective immune response depends on the large-scale, but carefully regulated, migration of T cells within and between lymphoid and peripheral tissues. This migration is tightly regulated by several factors, including the highly organized secondary lymphoid structure and the cellular expression of chemokine receptors and compartmentalized secretion of their cognate ligands (1). This balance between the anatomy and the ordered expression of cell surface and soluble proteins dictates the exquisite choreography of T-cell migration, and visualizing these dynamics of T-cell behavior in situ within the lymph nodes (LNs) is essential for understanding the mechanisms that mediate the generation of a productive antimicrobial or antitumoral immune response (1, 2). However, our understanding of the factors that regulate the anatomical program followed by endogenous antigen-specific effector T cells after an infection remains incomplete, especially with respect to the mechanisms that regulate egress kinetics of effector T cells from LN (2, 3).T-cell migration, even at steady state, is a highly regulated process (4). T-cell entry into the LN is controlled by G protein-coupled receptors (GPCRs) (3) such as CC chemokine receptor 7 (CCR7), which is also critical for the localization and retention of T cells within the LN paracortex (5, 6). Egress of naive T cells from the LN via the lymphatic vessels is regulated by the GPCR sphingosine-1-phosphate receptor-1 (S1PR1) (3) and adhesion molecules (4). S1PR1 is among four other GPCRs that bind to sphingosine-1-phosphate (S1P) with high affinity. S1PR1 is abundantly expressed in different cell types and tissues, including immune cells and endothelial cells (7). In addition to mediating lymphocyte egress, binding of S1P to S1PR1 and other receptors (S1PR2 to -5) on the cell surface initiates several signaling cascades that affect the functioning of many organ systems and control a multitude of biological ...

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