Finding a way out: S1P signaling and immune cell migration
Abstract
The signaling lipid sphingosine 1-phosphate (S1P) plays critical roles in an immune response. Drugs targeting S1P signaling have been remarkably successful in treatment of multiple sclerosis, and they have shown promise in clinical trials for colitis and psoriasis. One mechanism of these drugs is to block lymphocyte exit from lymph nodes, where lymphocytes are initially activated, into circulation, from which lymphocytes can reach sites of inflammation. Indeed, S1P can be considered a circulation marker, signaling to immune cells to help them find blood and lymphatic vessels, and to endothelial cells to stabilize the vasculature. That said, S1P plays pleiotropic roles in the immune response, and it will be important to build an integrated view of how S1P shapes inflammation. S1P can function so effectively because its distribution is exquisitely tightly controlled. Here we review how S1P gradients regulate immune cell exit from tissues, with particular attention to key outstanding questions in the field.
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LECs and BECs synthesize S1P, which binds S1PR1 on DCs and T cells to promote their mobilization toward initial LVs.
“LECs and BECs also synthesize S1P, which binds the S1P receptor type 1 (S1PR1) on DCs ( Figure 3a ) and T cells to promote their mobilization toward initial LVs (106, 107).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
When resting recirculating lymphocytes encounter their specific antigen in the lymph node, they rapidly express CD69, which binds S1PR1 and removes it from the cell surface.
“When resting recirculating lymphocytes encounter their specific antigen in the lymph node, they rapidly express the CD69 activation marker that binds S1PR1 and removes it from the cell surface (106).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
An S1P gradient is reinforced by the expression of S1P lyase in the lymph node that degrades S1P.
“Furthermore, an S1P gradient is reinforced by the expression of S1P lyase in the lymph node that degrades S1P (106).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
S1P is present in much higher concentrations in lymph and blood than in the lymph node parenchyma.
“Synthesized by endothelial cells, S1P is present in much higher concentrations in lymph and blood than in the lymph node parenchyma (106, 123).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
Lymphocytes residing in the lymph node parenchyma express high levels of S1PR1 that they use to sense the S1P gradient, resulting in lymph node egress.
“Lymphocytes that reside in the lymph node parenchyma express high levels of S1PR1 that they use to sense the S1P gradient, resulting in lymph node egress (106, 123).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
S1P is the primary chemoattractant that drives the exit of activated and recirculating lymphocytes from lymph nodes into efferent LVs.
“S1P is the primary chemoattractant that drives the exit of activated and recirculating lymphocytes from lymph nodes into efferent LVs (106, 122, 123).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
Higher levels of S1P in lymph and blood cause downregulation and desensitization of S1PR1 on lymphocytes, facilitating their entry into lymph nodes from afferent LVs and blood against S1P gradients.
“In contrast, the higher levels of S1P in lymph and blood cause downregulation and desensitization of S1PR1 on lymphocytes that facilitate their entry into lymph nodes from afferent LVs and blood against S1P gradients (106, 123).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [106]
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Transport and Immune Functions of the Lymphatic System.
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- Authors
- Baeyens, A. A. L., & Schwab, S. R.
- Affiliations
- New York University (US)
- ORCID
- Schwab, Susan R.
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2020-04-26
- Volume
- 38
- Issue
- 1
- Pages
- 759-784
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- OpenAlex
- W3019095110
- Cited by
- 123
- References
- 4
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 28 · 2023: 21 · 2022: 15 · 2021: 17 · 2020: 5
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA202025)
- National Institute of Allergy and Infectious Diseases (R01AI123308, R01AI085166)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- sphingosine-1-phosphate, S1P signaling, leukocyte migration, lymphocyte emigration, lymph nodes, lymphatic vessels, inflammation, multiple sclerosis, colitis, psoriasis
- MeSH terms
- Animals, Cell Movement, Humans, Immune System, Lymphocyte Activation, Lymphocytes, Lysophospholipids, Sphingosine, Signal Transduction, Biomarkers
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