Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. Here we show that Prf1−/− mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation. They suffer from multiple age-related disorders and lower survival. Strikingly, pharmacological elimination of senescent-cells by ABT-737 partially alleviates accelerated aging phenotype in these mice. In LMNA+/G609G progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival. Our findings shed new light on mechanisms governing senescent-cell presence in aging, and could motivate new strategies for regenerative medicine.
Checkpoint-blocking antibodies like those targeting the PD-1/PD-L1 pathway have revolutionized oncology. We developed radiotracers based on therapeutic checkpoint-blocking antibodies permitting sensitive and high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. ImmunoPET of naive mice revealed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes). Interestingly, PD-L1 was also detected in brown adipose tissue (BAT), confirming the notion that BAT is immunologically relevant. Under pathophysiological conditions, strong expression of the receptor/ligand pair was also found in non-lymphoid tissues. Both were specifically detected in malignant tumors. PD-1 was readily detected after combined immunoradiotherapy causing massive tumor infiltration by PD-1+ lymphocytes. PD-L1 tracer uptake was reduced in PD-L1 knockout tumors. Moreover, monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed robust upregulation in the lung. This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer.
Reef-building corals are famous for their spectacular colors, ranging from blue and green to yellow, pink, orange and red. Green fluorescent protein (GFP)-like proteins contribute to this coloration in a major way. They were initially discovered in nonbioluminescent, zooxanthellate anthozoa, including actiniaria, zoantharia, corallimorpharia and stolonifera [1][2][3][4], and subsequently recognized as major color determinants of hermatypic reef corals [5][6][7] and also of azooxanthellate anthozoans [8].In addition to GFP-like proteins from the anthozoa, the presence of symbionts also contributes to reef coloration. The brownish tones of cnidarians may arise from symbiotic algae of the genus Symbiodinium, the For a variety of coral species, we have studied the molecular origin of their coloration to assess the contributions of host and symbiont pigments. For the corals Catalaphyllia jardinei and an orange-emitting color morph of Lobophyllia hemprichii, the pigments belong to a particular class of green fluorescent protein-like proteins that change their color from green to red upon irradiation with 400 nm light. The optical absorption and emission properties of these proteins were characterized in detail. Their spectra were found to be similar to those of phycoerythrin from cyanobacterial symbionts. To unambiguously determine the molecular origin of the coloration, we performed immunochemical studies using double diffusion in gel analysis on tissue extracts, including also a third coral species, Montastrea cavernosa, which allowed us to attribute the red fluorescent coloration to green-to-red photoconvertible fluorescent proteins. The red fluorescent proteins are localized mainly in the ectodermal tissue and contribute up to 7.0% of the total soluble cellular proteins in these species. Distinct spatial distributions of green and cyan fluorescent proteins were observed for the tissues of M. cavernosa. This observation may suggest that differently colored green fluorescent protein-like proteins have different, specific functions. In addition to green fluorescent protein-like proteins, the pigments of zooxanthellae have a strong effect on the visual appearance of the latter species.Abbreviations cjarRFP, Catalaphyllia jardinei red fluorescent protein; EosFP, Eos fluorescent protein; FP, fluorescent protein; GFP, green fluorescent protein; lhemOFP, Lobophyllia hemprichii orange fluorescent protein; mcavRFP, Montastrea cavernosa red fluorescent protein; rPE, phycoerythrin from the red alga Fauchea sp.; scubRFP, Scolymia cubensis red fluorescent protein.
reactivity in F1 (A ϫ B) hosts. Although the mode of transfer of antigenic material from the transplanted, im-and Jo ¨rg Reimann † munogenic cells to host-derived APC during cross-prim-*Microbiology and Tumor Biology Center ing has not been elucidated, recent evidence for the Karolinska Institute shedding of antigenic vesicles (Zhou et al., 1992a; Ra-S-171 77 Stockholm poso et al., 1996) and for the release of immunogenic, Sweden apoptotic blebs (Casciola-Rosen et al., 1996) provides † Institute of Medical Microbiology interesting possibilities for antigen transfer to APC. Hu-University of Ulm ang et al. (1996b) recently studied cross-priming using D-89069 Ulm influenza virus nucleoprotein-transfected H-2 d tumor Federal Republic of Germany cells given to irradiated H-2 dxb mice rescued with bone marrow from TAP Ϫ/Ϫ H-2 b mice. These mice developed a normal T cell compartment (on the TAP ϩ/ϩ thymic epi-References processing compartment and thus efficiently capture those few MHC-I molecules that have escaped from the
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