SUMMARY Hypothalamic control of aging was recently proposed, but the responsible mechanisms still remain unclear. Here, following the observation that aging of mice started with a substantial loss of hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1, we developed several mouse models with ablation of these hypothalamic cells, each of them consistently displaying an acceleration in aging-like physiological changes or shortening in lifespan. Conversely, aging retardation and lifespan extension were achieved in mid-aged mice when locally implanted with healthy hypothalamic stem/progenitor cells that were genetically engineered to survive from aging-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells greatly contributed to exosomal miRNAs in the cerebrospinal fluid which declined over aging, while central treatment with healthy hypothalamic stem/progenitor cells-secreted exosomes led to slowdown of aging. In conclusion, aging speed is controlled significantly by hypothalamic stem cells partially through release of exosomal miRNAs.

CD4 + effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff actually adopt in frontline tissues in vivo , we applied single-cell transcriptome and chromatin analysis on colonic Teff cells, in germ-free or conventional mice, or after challenge with a range of phenotypically biasing microbes. Subsets were marked by expression of interferon-signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic T H subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as T H markers distributed in a polarized continuum, which was also functionally validated. Clones derived from single progenitors gave rise to both IFN-γ and IL17-producing cells. Most transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activity of AP1 and IRF transcription factor families, not the canonical subset master regulators T-bet, GATA3, RORγ.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus with latent and lytic reactivation cycles. The mechanism by which KSHV evades the innate immune system to establish latency has not yet been precisely elucidated. Toll-like receptors (TLRs) are the first line of defense against viral infections. Myeloid differentiation factor 88 (MyD88) is a key adaptor that interacts with all TLRs except TLR3 to produce inflammatory factors and type I interferons (IFNs), which are central components of innate immunity against microbial infection. Here, we found that KSHV replication and transcription activator (RTA), which is an immediate-early master switch protein of viral cycles, downregulates MyD88 expression at the protein level by degrading MyD88 through the ubiquitin (Ub)-proteasome pathway. We identified the interaction between RTA and MyD88 in vitro and in vivo and demonstrated that RTA functions as an E3 ligase to ubiquitinate MyD88. MyD88 also was repressed at the early stage of de novo infection as well as in lytic reactivation. We also found that RTA inhibited lipopolysaccharide (LPS)-triggered activation of the TLR4 pathway by reducing IFN production and NF-B activity. Finally, we showed that MyD88 promoted the production of IFNs and inhibited KSHV LANA-1 gene transcription. Taken together, our results suggest that KSHV RTA facilitates the virus to evade innate immunity through the degradation of MyD88, which might be critical for viral latency control. IMPORTANCEMyD88 is an adaptor for all TLRs other than TLR3, and it mediates inflammatory factors and IFN production. Our study demonstrated that the KSHV RTA protein functions as an E3 ligase to degrade MyD88 through the ubiquitin-proteasome pathway and block the transmission of TLRs signals. Moreover, we found that KSHV inhibited MyD88 expression during the early stage of de novo infection as well as in lytic reactivation. These results provide a potential mechanism for the virus to evade innate immunity. Innate immunity is triggered by pattern recognition receptors, including the Nod-like receptors, RIG-like receptors, Toll-like receptors (TLRs), and cytosolic DNA receptors (1-4). Innate immunity is the first-line defense against viral infection and works by detecting pathogen-associated molecular patterns on invading viruses and promoting the adaptive immune response. All TLRs have N-terminal leucine-rich repeats that recognize pathogens and a C-terminal Toll-interleukin-1 receptor (TIR) domain that mediates intracellular signaling to downstream TIR domain-containing adaptors, such as MyD88, MAL (MyD88 adaptor-like; also known as TIRAP), TRIF (TIR domain-containing adaptor protein inducing beta interferon [IFN-␤]; also known as TICAM1), and TRAM (TRIF-related adaptor molecule; also known as TICAM2) (5-14). All TLRs use MyD88 as an adaptor to transmit downstream signals, except TLR3, which uses TRIF as an adaptor. TLRs detect viral components, such as RNA, foreign DNA containing unmethylated CpG dinucleotides, and cytosolic double-...

No abstract