CD8⁺ memory T-cell inflation renders compromised CD4⁺ T-cell-dependent CD8⁺ T-cell immunity via naïve T-cell anergy

Whether inflation of CD8⁺ memory T (mT) cells, which is often derived from repeated prime-boost vaccinations or chronic viral infections in the elderly, would affect late CD8⁺ T-cell immunity is a long-standing paradox. We have previously established an animal model with mT-cell inflation by transferring ConA-stimulated monoclonal CD8⁺ T cells derived from Ova-specific T-cell-receptor transgenic OTI mice into irradiation-induced lymphopenic B6 mice. In this study, we also established another two animal models with mT-cell inflation by transferring, 1) ConA-stimulated monoclonal CD8⁺ T cells derived from lymphocytic choriomeningitis virus glycoprotein-specific T-cell-receptor transgenic P14 mice, and 2) ConA-stimulated polyclonal CD8⁺ T cells derived from B6.1 mice into B6 mice with irradiation-induced lymphopenia. We vaccinated these mice with recombinant Ova-expressing Listeria monocytogenes and Ova-pulsed dendritic cells, which stimulated CD4⁺ T cell-independent and CD4⁺ T-cell-dependent CD8⁺ T-cell responses, respectively, and assessed Ova-specific CD8⁺ T-cell responses by flow cytometry. We found that Ova-specific CD8⁺ T-cell responses derived from the latter but not the former vaccination were significantly reduced in mice with CD8⁺ mT-cell inflation compared to wild-type B6 mice. We determined that naïve CD8⁺ T cells purified from splenocytes of mice with mT-cell inflation had defects in cell proliferation upon stimulation in vitro and in vivo and upregulated T-cell anergy-associated Itch and GRAIL molecules. Taken together, our data reveal that CD8⁺ mT-cell inflation renders compromised CD4⁺ T-cell-dependent CD8⁺ T-cell immunity via naïve T-cell anergy, and thus show promise for the design of efficient vaccines for elderly patients with CD8⁺ mT-cell inflation.