Objectives: Neuroendocrine mediators impact the immune system,
including the mucosal immune system responsible for surveillance and protection
in the upper respiratory tract. Murine studies have demonstrated the
experience of social defeat (social disruption stress, SDR) before a primary
influenza virus challenge augmented immunological memory responses to viral re-challenge.
Patterning of immune memory is established by the immune response to a primary
infection, during which the CD8+T cell is principally responsible
for termination of viral replication. The present study was designed to
investigate potential mechanisms for memory enhancement.
Methods: Male C57BL/6 mice underwent SDR or were undisturbed (INF)
before intra-nasal infection with influenza A/PR/8/34. Daily two-hour
cycles entailed introduction of an aggressive mouse that defeated all resident
mice. Mice were infected after the sixth (final) cycle. Cells were isolated
post-infection and assessed via flow cytometry using a peptide-specific MHC I tetramer
to identify the immunodominant NP366 response.
Results: Exposure to SDR in the absence of infection increased
lung gene expression of innate cytokines IFNa and IFNb. Following infection, SDR mice had an increased number of lung NP366-74CD8+T
cells (p<0.05). The influx originated during the clonal expansion phase,
and at day 9 post-infection included more cells expressing an activated
phenotype: CD25+/CD62LLO NP366-74CD8+
in SDR mice versus the INF group. SDR mice consistently cleared influenza
virus earlier from lung tissue compared to INF group. Histologically, SDR mice
had increased mononuclear cell infiltrate, consolidation and cytopathic effects
in lung tissue compared to the INF group.
Conclusions: Social defeat, prior to primary viral infection, enhanced
virus-specific CD8+T cell memory. Enhanced memory was associated
with increased expansion of antigen-specific CD8+T cells during the
primary response, and with altered local factors, which may have contributed to
T cell activation and earlier clearance of virus from lung tissue in SDR
animals.
Supported by NIH grants F30DE17068-02,
RO1MH46801-13, T32DE014320-04.
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