Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD

Differences in salivary hormones and perception of exertion in elite women and men volleyball players during tournament.

BACKGROUND: Sports tournaments induce both psychological and physiological stress, which seems to be different between men and women. Competition induces anticipatory rises in testosterone and cortisol levels, which may affect performance and physical exertion during tournaments. The aim of this study was to compare the changes in salivary cortisol and testosterone concentrations between men and women during an official volleyball tournament and to test potential correlations between changes in these hormones and perceived exertion after match. METHODS: Three matches of each team were assessed in the group stage of the Men and Women South American Volleyball Championship. Salivary cortisol and testosterone levels were measured in the fasting state, before and after each match. The rate of perceived exertion (RPE) was assessed after each match. RESULTS: Fasting cortisol concentrations were higher in women than men (~25%, P<0.001) while fasting testosterone was higher in men than women (~46%, P<0.001). Cortisol concentration increased only after the second match in men (+53.7%, P<0.001). Testosterone concentration was low before and after the third match in men (P<0.001) while it was elevated after the third match in women (P=0.003). The rate of perceived exertion was correlated with the change in testosterone levels due to the matches in both women (r=0.33; P=0.04) and men (r=0.44; P=0.02), which was not observed for cortisol concentrations. CONCLUSIONS: These results indicate that women have higher fasting cortisol, but lower fasting testosterone concentrations than men during a volleyball tournament. Thus, hormonal responses of women and men are different and related to their effort during the matches

A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats.

Desminopathy is the most common intermediate filament disease in humans. The most frequent mutation causing desminopathy in patients is a R350P DES missense mutation. We have developed a rat model with an analogous mutation in R349P Des. To investigate the role of R349P Des in mechanical loading, we stimulated the sciatic nerve of wild-type littermates (WT) (n&nbsp;=&nbsp;6) and animals carrying the mutation (MUT) (n&nbsp;=&nbsp;6) causing a lengthening contraction of the dorsi flexor muscles. MUT animals showed signs of ongoing regeneration at baseline as indicated by a higher number of central nuclei (genotype: P&nbsp;&lt;&nbsp;.0001). While stimulation did not impact central nuclei, we found an increased number of IgG positive fibers (membrane damage indicator) after eccentric contractions with both genotypes (stimulation: P&nbsp;&lt;&nbsp;.01). Interestingly, WT animals displayed a more pronounced increase in IgG positive fibers with stimulation compared to MUT (interaction: P&nbsp;&lt;&nbsp;.05). In addition to altered histology, molecular signaling on the protein level differed between WT and MUT. The membrane repair protein dysferlin decreased with eccentric loading in WT but increased in MUT (interaction: P&nbsp;&lt;&nbsp;.05). The autophagic substrate p62 was increased in both genotypes with loading (stimulation: P&nbsp;&lt;&nbsp;.05) but tended to be more elevated in WT (interaction: P&nbsp;=&nbsp;.05). Caspase 3 levels, a central regulator of apoptotic cell death, was increased with stimulation in both genotypes (stimulation: P&nbsp;&lt;&nbsp;.01) but more so in WT animals (interaction: P&nbsp;&lt;&nbsp;.0001). Overall, our data indicate that R349P Des rats have a lower susceptibility to structural muscle damage of the cytoskeleton and sarcolemma with acute eccentric loading

TLR2 and TLR4 activation induces p38 MAPK-dependent phosphorylation of S6 kinase 1 in C2C12 myotubes.

Toll-like receptors 2 (TLR2) and 4 (TLR4) are present in the plasma membrane of skeletal muscle cells where their functions remain incompletely resolved. They are able to bind various extra-cellular ligands, such as FSL-1, lipopolysaccharide (LPS) and/or palmitic acid (PA). The purpose of this study was to investigate the link between PA, TLR2/4, and ribosomal S6 kinase 1 (S6K1) in C2C12 myotubes. Incubation with agonists of either TLR2 or TLR4, as well as incubation with high concentration of PA, led to an increase in S6K1 phosphorylation level. Canonical upstream kinases of S6K1, protein kinase B (PKB) and mammalian target of rapamycin complex 1 (mTORC1), were regulated in the opposite way by PA, indicating that those kinases were probably not involved. By using the SB202190 inhibitor, we evidenced that p38 MAPK was a key mediator of PA-induced phosphorylation of S6K1. Down-regulation of either tlr2 or tlr4 gene expression by small interfering RNAs prevented the activation of both p38 MAPK and S6K1 by FSL-1, LPS or PA. In summary, our results showed that TLR2 and TLR4 agonists are able to increase the level of S6K1 phosphorylation in a p38 MAPK dependent way in C2C12 myotubes. As PA induced the same intracellular signaling, we evidenced for the first time an atypical pathway for PA that is induced at the cellular membrane level and results in a higher phosphorylation state of S6K1