A molecular signature of lung-resident CD8⁺ T cells elicited by subunit vaccination

Natural infection as well as vaccination with live or attenuated viruses elicit tissue resident, CD8⁺ memory T cell (Trm) response. Trm cells so elicited act quickly upon reencounter with the priming agent to protect the host. These Trm cells express a unique molecular signature driven by the master regulators-Runx3 and Hobit. We previously reported that intranasal instillation of a subunit vaccine in a prime boost vaccination regimen installed quick-acting, CD8⁺ Trm cells in the lungs that protected against lethal vaccinia virus challenge. It remains unexplored whether CD8⁺ Trm responses so elicited are driven by a similar molecular signature as those elicited by microbes in a real infection or by live, attenuated pathogens in conventional vaccination. We found that distinct molecular signatures distinguished subunit vaccine-elicited lung interstitial CD8⁺ Trm cells from subunit vaccine-elicited CD8⁺ effector memory and splenic memory T cells. Nonetheless, the transcriptome signature of subunit vaccine elicited CD8⁺ Trm resembled those elicited by virus infection or vaccination. Clues to the basis of tissue residence and function of vaccine specific CD8⁺ Trm cells were found in transcripts that code for chemokines and chemokine receptors, purinergic receptors, and adhesins when compared to CD8⁺ effector and splenic memory T cells. Our findings inform the utility of protein-based subunit vaccination for installing CD8⁺ Trm cells in the lungs to protect against respiratory infectious diseases that plague humankind.