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Protection against Influenza A Virus by Memory CD8 T Cells Requires Reactivation by Bone Marrow-Derived Dendritic Cells¹

Paola Castiglioni^*, De Shon Hall^*, Erica L. Jacovetty^*,, Elizabeth Ingulli^*, and Maurizio Zanetti^2,*,

^* The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, Department of Pediatrics, and Biomedical Science Program, University of California San Diego, La Jolla CA 92093

Influenza A virus is the causative agent of an acute inflammatory disease of the airway. Although Abs can prevent infection, disease and death can be prevented by T cell-mediated immunity. Recently, we showed that protection against lethal influenza A (PR8/34) virus infection is mediated by central memory CD8 T cells (T_CM). In this study, using relB^–/– mice we began to investigate the role of bone marrow (BM)-derived dendritic cells (DCs) in the mechanism of protection. We found that in the absence of functional DCs, memory CD8 T cells specific for the nucleoprotein epitope (NP_366–374) fail to protect even after adoptive transfer into naive recipients. Through an analysis of Ag uptake, activation of memory CD8 T cells, and display of peptide/MHC complex by DCs in draining LNs and spleen early after virus infection, we established that lack of protection is associated with defective Ag presentation by BM-derived DCs and defective homing of memory T cells in the lymph nodes draining the airway tract. Collectively, the data suggest that protection against the influenza A virus requires that memory CD8 T cells be reactivated by Ag presented by BM-derived DCs in the lymph nodes draining the site of infection. They also imply that protection depends both on the characteristics of systemic adaptive immunity and on the coordinated interplay between systemic and local immunity.

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 RO1AI062894.

² Address correspondence and reprint requests to Dr. Maurizio Zanetti, University of California San Diego, 9500 Gilman Drive, Number 0815, La Jolla, CA 92093. E-mail address: mzanetti{at}ucsd.edu

³ Abbreviations used in this paper: NP, nucleoprotein; BM, bone marrow; BMC, BM chimera; DC, dendritic cell; EID₅₀, 50% egg infectious dose; LN, lymph node; T_CM, central memory T cell.