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Deviation from a Strong Th1-Dominated to a Modest Th17-Dominated CD4 T Cell Response in the Absence of IL-12p40 and Type I IFNs Sustains Protective CD8 T Cells¹

Nural N. Orgun^*, Meredith A. Mathis, Christopher B. Wilson^*, and Sing Sing Way^2,*

^* Department of Pediatrics and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195

The differentiation of naive CD4 T cells into specific effector subsets is controlled in large part by the milieu of cytokines present during their initial encounter with Ag. Cytokines that drive differentiation of the newly described Th17 lineage have been characterized in vitro, but the cytokines that prime commitment to this lineage in response to infection in vivo are less clear. Listeria monocytogenes (Lm) induces a strong Th1 response in wild-type mice. By contrast, we demonstrate that in the absence of IL-12p40 (or IFN-) and type I IFN receptor signaling, the Th1 Ag-specific CD4 T cell response is virtually abolished and replaced by a relatively low magnitude Th17-dominated response. This Th17 response was dependent on TGF-β and IL-6. Despite this change in CD4 T cell response, neither the kinetics of the CD4 and CD8 T cell responses, the quality of the CD8 T cell response, nor the ability of CD8 T cells to mediate protection were affected. Thus, generation of protective CD8 T cell immunity was resilient to perturbations that replace a strong Th1-dominated to a reduced magnitude Th17-dominated Ag-specific CD4 T cell response.

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 Institute of Child Health and Human Development/National Institutes of Health Grant K08HD51584, Infectious Disease Society of America Young Investigator Award, Puget Sound Partners for Global Health, and March of Dimes Basil O’Conner Research Award.

² Address correspondence and reprint requests to Dr. Sing Sing Way, Departments of Pediatrics and Microbiology, University of Minnesota School of Medicine, Center for Infectious Diseases and Microbiology Translational Research, 2001 6th Street Southeast, Room 3-212, Minneapolis, MN 55455. E-mail address: singsing{at}umn.edu

³ Abbreviations used in this paper: Lm, Listeria monocytogenes; WT, wild type; LLO, listeriolysin O.