Viral MHC class I inhibition evades protective tissue-resident memory CD8+ T cells (TRM) and influences TRM immunodominance within specific niches

Tissue-resident memory CD8+ T cells (TRM) confer rapid protection and immunity against viral infections. Many viruses have evolved mechanisms to inhibit MHCI presentation in order to evade effector CD8+ T cells, suggesting that these mechanisms may also apply to TRM-mediated protection. However, the effects of viral MHCI inhibition on the function and generation of TRM is unknown. We show that viral MHCI inhibition dampens immunodominance within the lung TRM pool, indicating an effect on the TRM repertoire, but this effect was not observed in the skin. In the presence of viral MHCI inhibition, the overall development of TRM is unaffected, yet is unexpectedly enhanced with local cognate antigen, while local cognate antigen is not required for TRM maintenance. Moreover, viral MHCI inhibition efficiently evades TRM effector functions. These findings suggest that vaccine strategies involving pure T-cell approaches may provide poor efficacy against viruses that target the MHCI pathway.