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The Absence of Lymphoid CD8⁺ Dendritic Cell Maturation in L-Selectin^–/– Respiratory Compartment Attenuates Antiviral Immunity¹

Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717

Intratracheal instillation of L-selectin-deficient (L-Sel^–/–) mice with an adenovirus 2 (Ad2) vector resulted in the lack of respiratory Ad2- or β-galactosidase-specific CTLs with concomitant long-lived β-galactosidase transgene expression in the lungs. The absence of Ag-specific CTLs was attributed to a deficiency in lymphoid CD11c⁺CD8⁺ dendritic cells (DCs) in the lower respiratory lymph nodes (LRLNs). To enable L-Sel^–/– CTL activity, cell-sorted L-Sel^–/–CD8⁺ T cells were cocultured with cell-sorted L-Sel^+/+CD8⁺ or CD8^– DCs or L-Sel^–/–CD8^– DCs. Only the CD8⁺ DCs restored CTL activity; L-Sel^–/–CD8^– DCs failed to support L-Sel^+/+ CTLs because these remained immature, lacking the ability to express costimulatory molecules CD40, CD80, or CD86. Although no lung CD8⁺ DCs were detected, the DC environment remained suppressive in L-Sel^–/– mice evident by the lack of CTL responses following adenoviral challenge with OVA in recipient L-Sel^–/– adoptively transferred with OT-1 CD8⁺ T cells. To assess whether the L-Sel^–/–CD8^– DCs could be induced into maturity, microbial stimulation studies were performed showing the failure of L-Sel^–/– LRLN to make matured DCs. When L-Sel^–/– mice were subjected in vivo to microbial activation before Ad2 vector dosing, CTL activity was restored stimulating the renewed presence of LRLN CD8⁺ DCs in L-Sel^–/– mice. These studies show that impairment of L-Sel^–/– DC maturation results in insufficient mature DCs that require microbial activation to restore increases in respiratory CD8⁺ DCs to support CTL responses.

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¹ This work was supported by Public Health Service Grant AI-55563 and in part by Montana Agricultural Station and U.S. Department of Agriculture Formula Funds. The Veterinary Molecular Biology Flow Cytometry Facility was in part supported by National Institutes of Health/National Center for Research Resources, Centers of Biomedical Excellence P20 RR-020185, and in part from a grant from M. J. Murdock Charitable Trust.

² Address correspondence and reprint requests to Dr. David W. Pascual, Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717-3610. E-mail address: dpascual{at}montana.edu

³ Abbreviations used in this paper: LN, lymph node; HNLN, head and neck LN; PNAd, peripheral node addressin; DC, dendritic cell; LRLN, lower respiratory LN; Ad2, adenovirus 2; i.t., intratracheal; CM, complete medium; βgal, β-galactosidase; CFDA, carboxy-fluorescein diacetate succinimidyl ester; DPBS, Dulbecco’s PBS; pDC, plasmacytoid DC; mDC, myeloid DC; cDC, conventional DC.