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Imatinib Mesylate Inhibits Antigen-Specific Memory CD8 T Cell Responses In Vivo¹

Parisa Sinai^*, Rance E. Berg^2,*, J. Marshall Haynie^*, Merrill J. Egorin, Robert L. Ilaria, Jr^3, and James Forman^4,*

^* Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Division of Hematology/Oncology, Department of Medicine, Simmons Cancer Center; and the Hammon Center For Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390; and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232

Imatinib mesylate (IM) is effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia. Because its influence on CD8 T cell responsiveness in vivo is unknown, we investigated the effects of IM by analyzing the response of OT-1 CD8 T cells to Listeria monocytogenes (LM) that express the cognate epitope OVA_257–264 (LM-OVA). In vitro, IM had no effect on Ag-specific expansion, cell division, cell cycle progression, or IFN- expression in naive or memory OT-1 T cells. However, IM induced apoptosis of naive and memory OT-1 T cells at doses of >5 µM. At 15 µM IM, OT-1 T cells did not survive in in vitro cultures. The primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered. In contrast, continuous IM treatment resulted in a diminished memory OT-1 response. The expression of IL-7R, a receptor required for memory cell survival, was lower (on OT-1 cells) in animals receiving IM. These results indicate that IM treatment affects the ability of the CD8 memory pool to respond to Ag and has the potential to increase susceptibility to infection.

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 National Institutes of Health Grant AI45764 (to J.F.).

² Current address: University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107.

³ Current address: Eli Lilly and Company, Indianapolis, IN 46285.

⁴ Address correspondence and reprint requests to Dr. James Forman, Center for Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390. E-mail address: james.forman{at}utsouthwestern.edu

⁵ Abbreviations used in this paper: IM, imatinib mesylate; AnnV, annexin V; 7-AAD, 7-aminoactinomycin D; CML, chronic myelogenous leukemia; ICS, intracellular cytokine staining; LM, Listeria monocytogenes; LM-OVA, LM expressing the OVA protein; LN, lymph node.

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