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An In Vivo Cytotoxicity Threshold for Influenza A Virus-Specific Effector and Memory CD8⁺ T Cells¹

John Stambas^2,*, Peter C. Doherty^*, and Stephen J. Turner^*

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Melbourne, Australia; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Influenza A virus infection of C57BL/6 (B6) mice is characterized by prominent CD8⁺ T cell responses to H2D^b complexed with peptides from the viral nucleoprotein (NP₃₆₆, ASNENMETM) and acid polymerase (PA₂₂₄, SSLENFRAYV). An in vivo cytotoxicity assay that depends on the adoptive transfer of peptide-pulsed, syngeneic targets was used in this study to quantitate the cytotoxic potential of D^bNP₃₆₆- and D^bPA₂₂₄-specific acute and memory CD8⁺ T cells following primary or secondary virus challenge. Both T cell populations displayed equivalent levels of in vivo effector function when comparable numbers were transferred into naive B6 hosts. Cytotoxic activity following primary infection clearly correlated with the frequency of tetramer-stained CD8⁺ T cells. This relationship looked, however, to be less direct following secondary exposure, partly because the numbers of CD8⁺D^bNP₃₆₆⁺ T cells were greatly in excess. However, calculating the in vivo E:T ratios indicated that in vivo lysis, like many other biological functions, is threshold dependent. Furthermore, the capacity to eliminate peptide-pulsed targets was independent of the differentiation state (i.e., primary or secondary effectors) and was comparable for the two T cell specificities that were analyzed. These experiments provide insights that may be of value for adoptive immunotherapy, where careful consideration of both the activation state and the number of effector cells is required.

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 a National Health and Medical Research Council Burnet Award (to P.C.D.), the American Lebanese Syrian Associated Charities, a National Health and Medical Research Council Program Grant (AI 299907), National Institutes of Health Grant AI170251, and by a University of Melbourne Early Career Researcher Grant (to J.S.). S.J.T. is a National Health and Medical Research Council R. D. Wright Fellow.

² Address correspondence and reprint requests to Dr. John Stambas, Department of Microbiology and Immunology, University of Melbourne, Parkville, 3010 Melbourne, Australia. E-mail address: jstambas{at}unimelb.edu.au

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; i.n., intranasal; NP, viral nucleoprotein; PA, acid polymerase; NA, neuraminidase; PI, propidium iodide; FSC, forward scatter; SSC, side scatter.

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