S1P₁ downregulation tailors CD8⁺ T‐cell residence time in lymph nodes to the strength of the antigenic stimulation

Abstract

T cells are sequestered for several days in lymph nodes following antigen recognition but the precise mechanism regulating their timing of egress is not fully understood. In particular, whether interactions with antigen-presenting cells (APCs) and/or strength of the TCR stimulation shape T-cell residence time is unclear. We report here that the probability of T-cell egress decreases upon stimulation with high affinity TCR ligands. In contrast, low affinity peptides favor early egress, a phenomenon that could be reversed by sustaining antigen availability. The delayed egress of high affinity T cells could not be accounted by physical sequestration by APCs. Instead, we found that the sphingosine-1-phosphate receptor (S1P ) downregulation mirrors the strength and persistence of the TCR stimulation, limiting egress of high affinity T cells. We propose that S1P acts as a rheostat to tailor T-cell residence time in the lymph node to the local availability of antigen and to optimize the expansion of high affinity T cells.

Transport Barriers Influence the Activation of Anti‐Tumor Immunity: A Systems Biology Analysis

“…Finally, we assume that immune checkpoint blockade is persistent and nearly complete, and the exhaustion rate of effector T cells is very small. [ 45 , 54 , 55 ] These assumptions simplified the analysis, allowing us to focus on the systemic transport limitations rather than biological impediments to T cell activation and killing. Where significant T cell exhaustion occurs, a continued antitumor immune response would require the activation of additional nT‐cell clones as previous effector T cells become ineffective.…”

“…The residence time in each lymph node is 10 h, and the residence times for the other organs are listed in Table S1 (Supporting Information). [ 44 , 45 ] We assume that any nT‐cell that enters the blood system of a lymph node will extravasate into the node via HECs. Once in the node, we use a threshold to determine whether the nT‐cell becomes activated based on the local level of antigen in that node.…”

The lymphatic vasculature: An active and dynamic player in cancer progression

“…After a few hours of scanning antigen‐presenting cells in the T cell zone for the presence of cognate antigen, most T cells will exit the LN again by exiting via the efferent lymphatic vessel. By contrast, if a T cell encounters its cognate antigen on an antigen‐presenting cell, it will become activated, proliferate, and differentiate, to give rise to millions of antigen‐specific effector cells, which after several days will also leave the LN 50,55–57 . Both naïve and antigen‐specific lymphocytes exit the LN parenchyma through blind‐ended lymphatic cortical sinuses that emerge adjacent to HEVs in the paracortex.…”

“…By contrast, if a T cell encounters its cognate antigen on an antigen‐presenting cell, it will become activated, proliferate, and differentiate, to give rise to millions of antigen‐specific effector cells, which after several days will also leave the LN. 50 , 55 , 56 , 57 Both naïve and antigen‐specific lymphocytes exit the LN parenchyma through blind‐ended lymphatic cortical sinuses that emerge adjacent to HEVs in the paracortex. The cortical sinuses merge into medullary sinuses, which further connect with the efferent lymphatic vessel leaving the LN.…”

Treatment of experimental autoimmune myasthenia gravis rats with FTY720 and its effect on Th1/Th2 cells

“…FTY720, also known as fingolimod, is a new generation immune suppressant that is extracted from the Traditional Chinese Medicine Cordyceps sinensis, with the major component ISP-I (also known as myriocin) having immune suppressing roles that induce lymphocyte apoptosis, accelerate matured lymphocyte nesting and inhibit translocation of T cells from the thymus to the peripheral blood circulation, and thus serving a role in transplantation immunity with strong effects and minor side effects (15). A recent study confirmed the role of FTY720 in regulating autoimmune diseases such as encephalomyelitis (16); however, the role of FTY720 in MG remained unknown. The aim of the present study was to investigate the role of FTY720 in MG and its underlying therapeutic mechanism, as well as providing a basis for the discovery of novel treatment approaches for MG.…”