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A7573 - Role of PD-1 Axis in Regulating Acute Anti-Influenza CD8 T Cell Response and Memory Formation
Author Block: K. Patel1, M. Ali2, S. F. Ngiow2, E. Wherry2; 1Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 2Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Rationale: PD-1 and PD-L1 are important targets for cancer immunotherapy and inhibition of the pathway leads to reinvigoration of exhausted, hypo-functional CD8 T cells in cancer and chronic infections. PD-1 is also expressed after T cell activation and the effects of PD-1 pathway blockade during acute infections such as influenza are not well understood. Prior work in mice with germline deficiency in either PD-1 or both PD-1 ligands, PD-L1 and PD-L2, demonstrated faster clearance of influenza and more antigen-specific CD8 T cells but protection against re-infection is impaired. How PD-1 and each of its ligands regulates the magnitude of CD8 T cell response in flu infection and how it impacts memory formation are unclear. In this study, we examine the role of PD-1 and both ligands early during influenza infection and the establishment of memory.
Methods: To study T cell activation, flu antigen specific CD8 T cells from wild type (WT) and PD-1 deficient (PD-1-/-) mice were co-adoptively transferred into WT recipient mice or, to study the role of PD-1 ligands, into recipient mice deficient for either or both PD-1 ligands (PD-L1-/-, PD-L2-/-, or PD-L1/L2-/-). CD8 T cell memory was assessed by infecting germline PD-1 -/- or WT mice and analyzing flu antigen specific CD8 T cells in the blood and lungs at late time points. Mice were infected with PR8 influenza strain and cells analyzed by flow cytometry.
Results: PD-1-/- CD8 T cells accumulate faster and express CD25 longer in draining lymph nodes than co-transferred WT CD8 T cells. Co-transfer of WT and PD-1-/- CD8 T cells into recipient PD-L2-/-mice led to this same phenotype as co-transfer into recipient WT mice, however PD-1-/- CD8 T cells were present in lower numbers than WT cells when co-transferred into PDL1-/- or PDL1/L2-/- recipient mice suggesting a disadvantage when both PD-1 and PD-L1 are absent. Germline PD1-/- mice had fewer flu antigen specific memory cells and memory cells in the blood had lower expression of CD62L which suggest a skew towards effector memory.
Conclusions: Absence of PD-1 on CD8 T cells leads to differential expression of CD25 and accumulation of cells faster than WT cells. PD-L2 is not needed for this phenotype while absence of PD-L1 in addition to PD-1 is detrimental to CD8 T cells. In the absence of PD-1, fewer memory cells are present and there is an alteration in memory markers in the blood.