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* Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; and
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105
Lymphocyte Activation Gene-3 (LAG-3) is a transmembrane protein that binds MHC class II, enhances regulatory T cell activity, and negatively regulates cellular proliferation, activation, and homeostasis of T cells. Programmed Death 1 (PD-1) also negatively regulates T cell function. LAG-3 and PD-1 are both transiently expressed on CD8 T cells that have been stimulated during acute activation. However, both LAG-3 and PD-1 remain on CD8 T cells at high levels after stimulation within tolerizing environments. Our previous data demonstrated that blockade of either LAG-3 or PD-1 using mAb therapy in combination with vaccination restores the function of tolerized Ag-specific CD8 T cells in models of self and tumor tolerance. It is unclear whether tolerized CD8 T cells coexpress PD-1 and LAG-3 or whether PD-1 and LAG-3 mark functionally distinct populations of CD8 T cells. In this study, we describe three populations of CD8 T cells activated under tolerizing conditions based on LAG-3 and PD-1 staining, each with distinct phenotypic and functional characteristics. From a mechanistic perspective, both Ag concentration and proinflammatory signals control the expression of LAG-3 and PD-1 phenotypes on CD8 T cells under activating and tolerizing conditions. These results imply that signaling through the PD-1 and LAG-3 pathways have distinct functional consequences to CD8 T cells under tolerizing conditions and manipulation of both Ag and cytokine signaling can influence CD8 tolerance through LAG-3 and PD-1.
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 C.G.D. is a Damon Runyon-Lilly Clinical Investigator. This work was also supported by National Institutes of Health R01 CA127153 (CGD), K08 CA096948 (CGD), and the Patrick C. Walsh Fund. D.M.P. is a Januey Scholar, holds the Seraph Chair for Cancer Research, and is supported in part by gifts from William and Betty Toperer, Dorothy Needle, and the Commonwealth Foundation. D.A.A.V. is supported by National Institutes of Health (NIH) (AI-39480), a Cancer Center Support CORE Grant (CA-21765), and the American Lebanese Syrian Associated Charities (ALSAC).
2 Address correspondence and reprint requests to Dr. Charles Drake, Johns Hopkins University School of Medicine, 1650 Orleans Street, Cancer Research Building 416, Baltimore, Maryland 21231. E-mail address: drakech{at}jhmi.edu
3 Abbreviations used in this paper: LAG-3, Lymphocyte Activation Gene-3; PD-1, Programmed Death 1; HA, hemagglutinin; IFA, incomplete Freund’s adjuvant; WT, wild type.
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