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* Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164; and
Trudeau Institute, Saranac Lake, NY 12983
The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR+/+ recipients, and the generation of CD45.2AhR–/–
CD45.1AhR+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.
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 the following research and training grants from National Institutes of Health: R01ES10619 and K02ES012409 (awarded to B.P.L.), HL63925 and AI055500 (awarded to D.L.W.), and T32AI07025 (awarded to J.J.N.). J.J.N. is the recipient of a Merck Research Scholar Award from the American Association of Colleges of Pharmacy and the Merck Company Foundation, a Seattle Chapter Achievement Rewards for College Scientists Scholarship, and a Rho Chi, Schering-Plough, American Foundation for Pharmaceutical Education First Year Graduate Fellowship.
2 Address correspondence and reprint requests to Dr. B. Paige Lawrence, Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642. E-mail address: paige_lawrence{at}urmc.rochester.edu
3 Abbreviations used in this paper: AhR, aryl hydrocarbon receptor; AhRE, Ah response element; BAL, bronchoalveolar lavage; DC, dendritic cell; EID50, egg ID50; GVH, graft-vs-host; i.n., intranasal; MLN, mediastinal lymph node; NP, nucleoprotein; PA, acid polymerase; PB-1, polymerase B1; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; Treg, regulatory T cell.
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