Our lab studies lymphocyte migration, with an emphasis on 3 questions: (1) What determines how long a lymphocyte stays in a given location, surveying for antigen or fighting infection, before it moves on? (2) How are the gradients that direct immune cell migration established?
(3) How do the trafficking requirements of normal and leukemic T cells differ, and can these differences be targeted therapeutically?
Much of our focus has been on how the residence time of T cells in lymphoid organs is determined. We have established that a gradient of the signaling lipid sphingosine 1-phosphate (S1P) is required to guide T cells out of lymphoid organs, defined many of the key cells and enzymes that control this gradient, and developed novel tools to map the gradient. Future work will assess how S1P gradients are regulated during an immune response. With this research, we hope to provide fundamental insight into how lipid gradients are shaped. We also hope that this work will translate to improved therapies for inflammatory disease. Drugs targeting S1P signaling are used clinically as immune suppressants. By blocking exit from lymphoid organs, these drugs prevent activated T cells from reaching organs that are subject to autoimmune attack. These drugs may have further anti-inflammatory effects. However, because S1P also regulates vascular stability and heart rate, side-effects are a serious concern. By defining how S1P gradients are regulated, we may identify targets that would allow spatially specific modulation of S1P signaling.
We have also recently turned our attention to trafficking of transformed T cells through lymphoid organs, using a model of T cell acute lymphoblastic leukemia (T-ALL). Our first experiments tested the hypothesis that blocking S1P receptor signaling would prevent T-ALL from leaving the lymphoid organs and metastasizing to the brain. This was not the case, and raised the fascinating question of how migration of leukemic T cells differs from normal cells. We found, by contrast, that loss of signaling through the chemokine receptor CXCR4 after T-ALL onset decimates the leukemia in both murine and human xenograft models of disease, an unexpected result as CXCR4 plays relatively subtle roles in normal T cell development and peripheral T cell maintenance. Because CXCR4 antagonists are in clinical trials for other cancers, our results may quickly translate to an effective and relatively non-toxic therapy for this aggressive disease. Future work will define additional trafficking requirements for T-ALL, particularly for metastasis to the central nervous system.
Willy Ramos-Perez, a graduate student in the lab, developed a reporter to measure S1P gradients in tissues. Using this reporter, we have found that S1P distribution is exquisitely tightly controlled, and that standard “rules of thumb” do not predict the levels of signaling-available lipid. Signaling lipids are notoriously difficult to track, because lipids are not encoded genetically and because many lipids play dual roles inside the cell as metabolic intermediates and outside the cell as signaling molecules. To our knowledge, the S1P reporter is the first tool to map a lipid in situ, and the principles we used may be broadly applicable to other elusive ligands. (Ramos-Perez et al., Nature Immunology, 2015)
Alejandra Mendoza, a graduate student in the lab, found that the S1P transporter SPNS2 is required to secrete lymph but not blood S1P. Her work revealed SPNS2 as novel target for immune suppressive drugs that may block exit of activated T cells from lymph nodes with minimal vascular and cardiac side-effects. (Mendoza et al., Cell Reports, 2012)
Lauren Pitt, a post-doctoral researcher in the lab, found that CXCR4 antagonism blocks expansion of T-ALL in mouse and primary xenograft models of disease. (Pitt et al., Cancer Cell, 2015)
The Schwab Lab
SKIRBALL INSTITUTE OF BIOMOLECULAR MEDICINE