Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs

Abstract

The extracellular lysophospholipase D autotaxin (ATX) and its product, lysophosphatidic acid, have diverse functions in development and cancer, but little is known about their functions in the immune system. Here we found that ATX had high expression in the high endothelial venules of lymphoid organs and was secreted. Chemokine-activated lymphocytes expressed receptors with enhanced affinity for ATX, which provides a mechanism for targeting the secreted ATX to lymphocytes undergoing recruitment. Lysophosphatidic acid induced chemokinesis in T cells. Intravenous injection of enzymatically inactive ATX attenuated the homing of T cells to lymphoid tissues, probably through competition with endogenous ATX and exertion of a dominant negative effect. Our results support the idea of a new and general step in the homing cascade in which the ectoenzyme ATX facilitates the entry of lymphocytes into lymphoid organs.

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Figure 1: Expression of ATX transcripts by mouse tissues.
Figure 2: Localization of ATX protein in lymphoid organs.
Figure 3: Secretion of ATX by HECs and transfected MDCK cells.
Figure 4: Integrin dependency of the binding of ATX to human T cells.
Figure 5: Effects of LPA on human T cells.
Figure 6: Migration of T cells to and within lymphoid organs in the presence of exogenous ATX.

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Acknowledgements

We thank B. Fuss (Virginia Commonwealth University Medical Center) for polyclonal anti–rat ATX; J.G. Cyster (University of California, San Francisco) for monoclonal anti–mouse α4 and anti–mouse αL and for rat insulin promoter–B lymphocyte chemokine mice; J. Bluestone (University of California, San Francisco) for nonobese diabetic mice; M. Singer and D. Tsay for assistance with homing assays; and E.J. Goetzl and J.G. Cyster for advice and critical reading of this manuscript. Supported by the National Institute of Health (RO1-GM57411 and RO1-GM23547 to S.D.R.) and the Uehara Memorial Foundation, Japan (H.K.).

Author information

H.K. and S.D.R. conceptualized and designed the research and prepared the manuscript; S.D.R. supervised the research and provided intellectual guidance; H.K. did experiments and analyzed data; R.N. and R.K. participated in the early phases of this project; Y.M. quantified ATX homing; and M.D.G. supervised the in situ hybridization.

Correspondence to Steven D Rosen.

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Kanda, H., Newton, R., Klein, R. et al. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 9, 415–423 (2008). https://doi.org/10.1038/ni1573

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