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Analyses of healthy tissue reveal signatures that identify resident memory CD8+ T cells (TRM), which survey tissues without recirculating. The density of TRM phenotype cells within solid tumors correlates favorably with prognosis, suggesting that intratumoral residents control cancer. However, residence has not been directly tested, and intratumoral TRM phenotype cells could instead reflect aspects of the microenvironment that correlate with prognosis. Using a breast cancer model in mice, we found that conventional TRM markers do not inform the tumor residence of either bystander or tumor-specific cells, which exhibit further distinct phenotypes in the tumor microenvironment and healthy mammary tissue. Rather, tumor-specific, stem progenitor CD8+ T cells migrate to tumors and become resident while acquiring select markers of exhaustion. These data indicate that tonic antigen stimulation and the tumor environment drive distinct programs of residence compared with healthy tissues and that tumor immunity is sustained by continued migration of tumor-specific stem cells. Editor's summary: The phenotype of resident memory T cells (TRM) differs between tissues but how cancer impacts the residence signature of tumor-infiltrating T cells is uncertain. Gavil et al. analyzed the phenotype and migration of mouse CD8 T cells from normal mammary fat pads or breast carcinoma tissue. The tumor-infiltrating CD8 T cells shared some typical TRM markers, but these markers were not predictive of stable residence within the tumor. Instead, the tumor microenvironment and the accompanying chronic antigen stimulation ushered in a distinct residence program including up-regulation of the exhaustion markers CD39 and Tim-3. The observed intersection of T cell residence and exhaustion programs within tumors provides fresh insights into how intratumoral CD8 T cell signatures are connected to cancer immunotherapy responses. —Ifor R. Williams [ABSTRACT FROM AUTHOR]

Respiratory tract resident memory T cells (TRM), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory TRM. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron–based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell–mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 TRM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node TRM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung TRM. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung TRM that can be further expanded by an additional intranasal immunization. Boosting up flu-specific lung T cells: Despite the rapid embrace of mRNA vaccine technologies catalyzed by the COVID-19 pandemic, the extent of the resident memory T cell (TRM) response in the lung after different routes of mRNA vaccination remains uncertain. By immunizing mice with a self-amplifying mRNA vaccine for influenza nucleoprotein encapsulated in dendritic nanoparticles, Künzli and O'Flanagan et al. assessed how various routes of vaccine administration affected CD4 and CD8 TRM responses. While intramuscular prime and boost immunizations were sufficient to induce respiratory TRM, an additional intranasal boost further expanded both circulating and lung resident memory CD4 and CD8 T cells. These findings indicate that optimization of the routes of administration and sequence of mRNA vaccine doses can elicit robust antibody and lung TRM responses to pathogenic respiratory viruses. –IRW [ABSTRACT FROM AUTHOR]

Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection., After encounter with antigen, CD8 T cells differentiate into effector cells, which form a crucial arm of the adaptive immune response against intracellular pathogens through the action of cytokines and [...]

The pathogen recognition theory dictates that, upon viral infection, the innate immune system first detects microbial products and then responds by providing instructions to adaptive CD8 T cells. Here, we show in mice that tissue resident memory CD8 T cells (TRM cells), non-recirculating cells located at common sites of infection, can achieve near-sterilizing immunity against viral infections by reversing this flow of information. Upon antigen resensitization within the mouse female reproductive mucosae, CD8+ TRM cells secrete cytokines that trigger rapid adaptive and innate immune responses, including local humoral responses, maturation of local dendritic cells, and activation of natural killer cells. This provided near-sterilizing immunity against an antigenically unrelated viral infection. Thus, CD8+ TRM cells rapidly trigger an antiviral state by amplifying receptor-derived signals from previously encountered pathogens. [ABSTRACT FROM AUTHOR]

The pathogen recognition theory dictates that, upon viral infection, the innate immune system first detects microbial products and then responds by providing instructions to adaptive CD8 T cells. Here, we show in mice that tissue resident memory CD8 T cells (T(RM) cells), non-recirculating cells located at common sites of infection, can achieve near-sterilizing immunity against viral infections by reversing this flow of information. Upon antigen resensitization within the mouse female reproductive mucosae, CD8(+) T(RM) cells secrete cytokines that trigger rapid adaptive and innate immune responses, including local humoral responses, maturation of local dendritic cells, and activation of natural killer cells. This provided near-sterilizing immunity against an antigenically unrelated viral infection. Thus, CD8(+) T(RM) cells rapidly trigger an antiviral state by amplifying receptor-derived signals from previously encountered pathogens., (Copyright © 2014, American Association for the Advancement of Science.)