Francesca Rossiello, Giada Cicio, Sara Sepe, Alexandra Mancheno-Ferris, Valeria Cancila, Arianna Castellini, Federica Rey, Giorgio Bertolazzi, Alessia Oppezzo, Eugenia Marinelli, Matteo Cabrini, Alessia di Lillo, Sara Tavella, Ilaria Rosso, Francesca M Buffa, Claudio Tripodo, Fabrizio d'Adda di Fagagna
We applied this method to a cohort of SIV-vaccinated rhesus macaques (RMs). We performed SIV-infected cell recognition assays to identify the SIV-specific TCRs for each RM. We used these TCRs to subset SIV-specific cells and perform precise contrasts. Despite identical vaccination, we identified clone- and subject-level variability in their cytotoxic differentiation and cytokine production after incubation with SIV-infected targets. Per clonotype, the percentage of cells that responded after antigen exposure varied widely. Finally, we used TCRs as barcodes to precisely map the in vivo activity of CD8+ T cells 48-120H after SIV challenge. Precise TCR-based identification separated Ag-specific and bystander effects, measuring tissue-specific responses of SIV-specific T cells within 48 hours of infection.
Telomere dysfunction and the telomeric DNA damage response (tDDR) activation correlate with aging and age-related diseases, including idiopathic pulmonary fibrosis (IPF). However, a causal role for tDDR in IPF pathogenesis has not been determined. IPF patients frequently bear germline mutations in telomerase genes, critically short telomeres, and markers of tDDR and cellular senescence. We previously demonstrated that telomeric antisense-oligonucleotides (tASOs) targeting telomeric non-coding RNAs are selective tDDR inhibitors. Here, we employed late-generation telomerase knockout mice as a genetic model of IPF. Systemic tASOs treatment reduces DDR-including in stem/progenitor cells-inflammation, and lung fibrosis in young, adult, and old mice. Markers of DDR correlate with lung pathology, and tDDR inhibition normalizes molecular and pathological phenotypes, uncoupling telomere lengths from their deleterious consequences. Transcriptomic changes in telomerase knockout mice recapitulate those observed in normal aged mice and in IPF patients, and they are reversed upon tDDR inhibition. These results highlight the pathogenic causative relevance of tDDR activation in IPF pathogenesis and support tASOs as a promising therapeutic strategy for IPF and for telomere biology diseases.