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Induction of a VLA-2 (CD49b)-Expressing Effector T Cell Population by a Cell-Based Neuroblastoma Vaccine Expressing CD137L¹

Xiaocai Yan^*,, Bryon D. Johnson^*, and Rimas J. Orentas^2,*,

^* Department of Pediatrics, Section of Hematology-Oncology, Medical College of Wisconsin Milwaukee, WI 53226; and The Children’s Research Institute, Children’s Hospital of Wisconsin, Milwaukee, WI 53226

In malignancies where no universally expressed dominant Ag exists, the use of tumor cell-based vaccines has been proposed. We have modified a mouse neuroblastoma cell line to express either CD80 (B7.1), CD137L (4-1BBL), or both receptors on the tumor cell surface. Vaccines expressing both induce a strong T cell response that is unique in that among responding CD8 T cells, a T effector memory cell (T_EM) response arises in which a large number of the T_EM express the -chain of VLA-2, CD49b. We demonstrate using both in vitro and in vivo assays that the CD49b⁺ CD8 T cell population is a far more potent antitumor effector cell population than nonfractionated CD8 or CD49b^– CD8 T cells and that CD49b on vaccine-induced CD8 T cells mediates invasion of a collagen matrix. In in vivo rechallenge studies, CD49b⁺ T cells no longer expanded, indicating that CD49b T_EM expansion is restricted to the initial response to vaccine. To demonstrate a mechanistic link between the expression of costimulatory molecules on the vaccine and CD49b on responding T cells, we stimulated naive T cells in vitro with artificial APC expressing different combinations of anti-CD3, anti-CD28, and CD137L. Although some mRNA encoding CD49b was induced by combining anti-CD3 with anti-CD28 or CD137L, the highest level was induced when all three signals were present. This indicates that CD49b expression results from additive costimulation and that the level of CD49b message serves as an indicator of the effectiveness of T cell activation by a cell-based vaccine.

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 U.S. Public Health Service Grant CA100030, American Cancer Society Internal Research Grant IRG-170, and the Midwest Athlete’s Against Childhood Cancer (MACC Fund, Inc., Milwaukee, WI).

² Address correspondence and reprint requests to Dr. Rimas J. Orentas at the current address: Lentigen Corp., 1450 South Rolling Road, Baltimore, MD 21227. E-mail address: rimas.orentas{at}lentigen.com

³ Abbreviations used in this paper: aAPC, artificial APC; HPRT, hypoxanthine phosphoribosyltransferase; BM, bone marrow; dLN, draining lymph node; DP, double positive; T_EM, effector memory T cell; T_CM, central memory T cell.