Division of labor between subsets of lymph node dendritic cells determines the specificity of the CD8⁺ T-cell recall response to influenza infection.

Cytotoxic T lymphocytes (CTLs) are important targets for vaccines against a wide variety of infections that enter the body via mucosal tissues. To induce effective immunity these vaccines must include the most protective epitopes and elicit rapid recall responses at the site of infection. Although live attenuated viruses are sometimes used to induce cellular immunity against recurrent influenza infections, the mechanisms that determine the magnitude of the response to individual viral components are very poorly defined. Heterosubtypic infections in C57BL/6 mice illustrate an additional level of complexity, when the antigen specificity of the response shifts dramatically between primary and secondary challenge. This model provides a unique opportunity to identify the mechanisms that regulate memory CD8(+) T-cell reactivation in vivo and control the specificity of the recall response by pathogen-specific CTL. We show that multiple factors contribute to the changing pattern of immunodominance during secondary infection, including the location of the memory CD8(+) T cells at the time of reinfection and their ability to directly recognize migratory CD103(+) DCs as they arrive in the lung draining LN.

In situ imaging reveals different responses by naïve and memory CD8 T cells to late antigen presentation by lymph node DC after influenza virus infection.

Pulmonary influenza infection causes prolonged lymph node hypertrophy while processed viral antigens continue to be presented to virus-specific CD8 T cells. We show that naïve, but not central/memory, nucleoprotein (NP)-specific CD8 T cells recognized antigen-bearing CD11b(+) DC in the draining lymph nodes more than 30 days after infection. After these late transfers, the naïve CD8 T cells underwent an abortive proliferative response in the mediastinal lymph node (MLN), where large clusters of partially activated cells remained in the paracortex until at least a week after transfer. A majority of the endogenous NP-specific CD8 T cells that were in the MLN between 30 and 50 days after infection also showed signs of a continuing response to antigen stimulation. A high frequency of endogenous NP-specific CD8 T cells in the MLN indicates that late antigen presentation may help shape the epitope dominance hierarchy during reinfection.