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LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis¹

Creg J. Workman^*, Yao Wang^*, Karim C. El Kasmi^2,, Drew M. Pardoll, Peter J. Murray, Charles G. Drake and Dario A. A. Vignali^3,*

^* Department of Immunology, and Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231

Lymphocyte activation gene 3 (LAG-3) is a CD4-related, activation-induced cell surface molecule expressed by various lymphoid cell types and binds to MHC class II with high affinity. We have previously shown that LAG-3 negatively regulates the expansion of activated T cells and T cell homeostasis, and is required for maximal regulatory T cell function. In this study, we demonstrate for the first time that LAG-3 is also expressed on CD11c^low/B220⁺/PDCA-1⁺ plasmacytoid dendritic cells (pDCs). Lag3 expression, as determined by real time PCR, was 10-fold greater in pDCs than in either regulatory T cells or activated T effector cells. Activated pDCs also generate 5 times more sLAG-3 than activated T cells. LAG-3-deficient pDCs proliferate and expand more than wild-type pDCs in vivo in response to the TLR9 ligand, CpG. However, the effect of LAG-3 appears to be selective as there was no effect of LAG-3 on the expression of MHC class II, TLR9, and chemokine receptors, or on cytokine production. Lastly, adoptive transfer of either Lag3^+/+ or Lag3^–/– T cells plus or minus Lag3^+/+ or Lag3^–/– pDCs defined a role for LAG-3 in controlling pDC homeostasis as well as highlighting the consequences of deregulated Lag3^–/– pDCs on T cell homeostasis. This raised the possibility of homeostatic reciprocity between T cells and pDCs. Collectively, our data suggests that LAG-3 plays an important but selective cell intrinsic and cell extrinsic role in pDC biology, and may serve as a key functional marker for their study.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the National Institutes of Health (NIH) (AI39480 to D.A.A.V., AI058156 to D.M.P., and AI62921 to P.J.M.), a Cancer Center Support CORE grant (CA-21765), and the American Lebanese Syrian Associated Charities (ALSAC) (to P.J.M. and D.A.A.V.).

² Current address: Department of Anesthesiology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262.

³ Address correspondence and reprint requests to Dr. Dario Vignali, Department of Immunology, St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. E-mail address: dario.vignali{at}stjude.org

⁴ Abbreviations used in this paper: LAG-3, lymphocyte activation gene 3; Treg, regulatory T cell; sLAG-3, soluble LAG-3; DC, dendritic cell; pDC, plasmacytoid DC; qPCR, quantitative PCR.