Introduction: S1PR1 drives T cells to migrate from thymus to blood, and from lymph node (LN) to efferent lymphatics. Whether S1PR1 or other S!PRs regulate T cell migration from tissues into afferent lymphatics and draining LN is unknown. We hypothesized that different S1PRs are utilized by CD4 T cells and lymphatic endothelial cells (LECs) for T cell trafficking from tissues through afferent lymphatics.

Methods: CFSE-labeled CD4 T cells treated with S1PR antagonists were adoptively transferred into mice, and migration to the draining popliteal LN enumerated. Mouse and human primary LEC, and blood endothelial and LEC lines were used to assess chemokine signals, adhesion molecules and S1PR function in vitro.

Results: S1P, unlike other chemokines, selectively promoted human and murine CD4 T cell migration across LEC, but not blood endothelial cells, by regulating T cell-LEC interactions. CD4 T cell migration toward S1P was dependent on both chemokinesis and chemotaxis, but not chemorepulsion, and these movements were regulated by S1PR1 and S1PR4. S1PR1 and S1PR4 specific antagonists each blocked migration at the level of the T cell, but did not affect LEC's functional ability to promote CD4 T cell migration. In contrast, an S1PR2 antagonist specifically decreased LEC monolayer permeability while blocking LEC's ability to promote CD4 T cell migration. In vivo migration assays showed that anti-S1P mAb inhibited CD4 T cell homing to LN. S1PR1 and S1PR4 antagonists specifically inhibited T cell migration into the draining LN, while pretreatment of tissues with the S1PR2 antagonist inhibited migration. Inflammatory conditions increased tissue S1P and TNFa, and S1P and TNFa increased VCAM-1 expression by LEC. Increased VCAM-1 and VLA-4 in turn increased CD4 T cell migration toward S1P, and enhanced migration was prevented by anti-VCAM-1 or anti-VLA-4 blocking mAbs.

Conclusions: CD4 T cells and LEC utilized distinct S1PRs to regulate migration across afferent lymphatics, in a VCAM-1 and VLA-4 dependent fashion. S1P engages active processes in both T cells and LEC to promote migration. These results demonstrate unique roles for S1P and S1PRs in regulating T cell and LEC functions in migration from tissues to LN, and that distinct receptors are used compared to thymic or efferent LN migration. These findings suggest new and specific drug targets for regulating lymphatic migration in immunity and tolerance.

CITATION INFORMATION: Xiong Y, Brinkman C, Hippen K, Blazar B, Bromberg J. CD4 T Cell Migration Across Lymphatic Endothelium Is Enhanced by Sphingosine 1-Phosphate (S1P) and Differentially Regulated by S1P Receptors (S1PR). Am J Transplant. 2017;17 (suppl 3).

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