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IL-12-Programmed Long-Term CD8⁺ T Cell Responses Require STAT4¹

Qingsheng Li^*, Cheryl Eppolito^*, Kunle Odunsi and Protul A. Shrikant^2,*

^* Department of Immunology and Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263

Immunological adjuvants activate innate immune cells for Ag presentation and elicitation of cytokines like IL-12 that promote T cell expansion and effector differentiation. An important but elusive aim for most immunization strategies is to produce memory T cells that provide durable immunity. Recent evidence demonstrates that the context of Ag presentation instructionally programs T cells for short- and long-term responses. However, the role and mechanisms by which cytokines like IL-12 condition CD8 T cells for long-term responses remain relatively uncharacterized. In this study, we show that brief exposure (20 h) of naive TCR-transgenic CD8 cells to IL-12 during Ag stimulation leads to transient phosphorylation of STAT4 for robust effector differentiation. Moreover, the IL-12-induced STAT4 engenders greater clonal expansion of the Ag-activated CD8 cells by regulating the expression of the transcriptional factor Bcl3- and Bcl2-related genes that promote survival of Ag-activated CD8 cells. Remarkably, the IL-12-conditioned CD8 T cells demonstrate increased sensitivity to IL-7 and IL-15, whereby they are rendered "fit" for homeostatic self-renewal as well as augmented CD4-dependent recall responses that are effective at controlling Salmonella infection in vivo. This information provides new insights into mechanisms by which IL-12 conditions CD8 T cells for long-term immunity, which is likely to benefit development of new strategies for the use of IL-12 in infectious diseases and cancer.

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 in part by National Institutes of Health Grant (CA104645-02; to P.A.S.), and Cancer Research Institute Anna-Marie Kellen Clinical Investigator Award (to K.O.).

² Address correspondence and reprint requests to Dr. Protul A. Shrikant, Department of Immunology, Roswell Park Cancer Institute, 322 Cancer Cell Center, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: Protul.Shrikant{at}roswellpark.org

³ Abbreviations used in this paper: PI, propidium iodide; ICS, intracytoplasmic staining; WT, wild type; KO, knockout.

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