RESUMEN
Tissue-resident memory T (T RM ) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive T RM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 T RM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus T RM signature of 60 genes across skin and siIEL that can effectively distinguish T RM from circulating T cell populations, providing a more specific T RM signature than what was previously generated by comparing bulk T RM to naïve or non-tissue resident memory populations. This updated T RM signature included the AP-1 transcription factor family members Fos, Fosb and Fosl2 . Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature T RM . CyCIF tissue imaging detected nuclear co-localization of AP-1 members Fosb and Junb in resting CD8 T RM >100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in T RM biology and suggests a novel mechanism for rapid reactivation of resting T RM in tissue upon antigen encounter.
RESUMEN
Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses. Comparisons of s.s. with intradermal, subcutaneous, or intramuscular routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. immunization compared to intra-tracheal immunization with MVAOVA and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization. Overall, our data suggest that heterologous MVA vectors immunized via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.
RESUMEN
We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1ß-/-, IL1α-/-, and IL1R1-/- mice. Tumors grew progressively in IL1R-/- and IL1α-/- mice but were often absent in IL1ß-/- mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages. Antibodies to IL1ß prevented tumor growth in wild-type (WT) mice but not in IL1R1-/- or IL1α-/- mice. Antibodies to IL1α promoted tumor growth in IL1ß-/- mice and reversed the tumor-suppressive effect of anti-IL1ß in WT mice. Depletion of CD8+ T cells and blockade of lymphocyte mobilization abrogated the IL1ß-/- tumor suppressive effect, as did crossing IL1ß-/- mice to SCID or Rag1-/- mice. Finally, blockade of IL1ß synergized with blockade of PD-1 to inhibit tumor growth in WT mice. These results suggest that IL1ß promotes tumor growth, whereas IL1α inhibits tumor growth by enhancing T-cell-mediated antitumor immunity.
