PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow.

Programmed death ligand 1 (PD-L1) has been shown to be inducibly expressed on neutrophils to suppress host immunity during polymicrobial sepsis, virus and parasite infections. However, the role of PD-L1 on neutrophil-mediated antifungal immunity remains wholly unknown. Here, we show that the expression of PD-L1 on murine and human neutrophils was upregulated upon the engagement of C-type lectin receptor Dectin-1 with its ligand ß-glucans, exposed on fungal pathogen Candida albicans yeast. Moreover, ß-glucan stimulation induced PD-L1 translocation into nucleus to regulate the production of chemokines CXCL1 and CXCL2, which control neutrophil mobilization. Importantly, C. albicans infection-induced expression of PD-L1 leads to neutrophil accumulation in bone marrow, through mediating their autocrine secretion of CXCL1/2. Furthermore, neutrophil-specific deficiency of PD-L1 impaired CXCL1/2 secretion, which promoted neutrophil migration from bone marrow into the peripheral circulation, thereby conferring host resistance to C. albicans infection. Finally, either PD-L1 blockade or pharmacological inhibition of PD-L1 expression significantly increased neutrophil release from bone marrow to enhance host antifungal immunity. Our data together indicate that activation of Dectin-1/PD-L1 cascade by ß-glucans inhibits neutrophil release from bone marrow reserve, contributing to the negative regulation of antifungal innate immunity, which functions as a potent immunotherapeutic target against life-threatening fungi infections.

Favorable colorectal cancer mortality-to-incidence ratios in countries with high expenditures on health and development index: A study based on GLOBOCAN database.

BACKGROUND: Global variation in the incidence and outcomes of colorectal cancer (CRC) is associated with many factors, among which screening policies and early treatment play substantial roles. However, screening programs and intense treatment are expensive and require good health care systems. For CRC, no clear association has yet been established between clinical outcomes and health care disparities. METHOD: We used the mortality-to-incidence ratio (MIR) of CRC as a measure of clinical outcomes for comparison with the Human Development Index (HDI), current health expenditure (CHE), and current health expenditure as a percentage of gross domestic product (CHE/GDP) using linear regression analyses. We included 171 countries based on data from the GLOBOCAN 2018 database. RESULTS: We found that the regions with the lowest MIRs for CRC are Oceania and North America. A significant correlation was observed between incidence, mortality and HDI, CHE, and CHE/GDP among the countries enrolled. Furthermore, lower MIRs of CRC significantly correlated with higher HDI, CHE, and CHE/GDP (P < 0.001, P < 0.001, and P < 0.001, respectively). CONCLUSION: : CRC MIRs tend to be most favorable in countries with high health care expenditures and a high HDI.

[Construction and identification of recombinant adenoviral vector encoding B7-H4 gene].

OBJECTIVE: To construct the recombinant adenovirus containing B7-H4 gene with AdEasy XL system and to identify its biological activities. METHODS: The full-length mouse B7-H4 gene was amplified by RT-PCR from C57 mouse lung and put into T vector, then verified by sequencing. Digested with Xhol I and EcoR V the B7-H4 gene was inserted into pshuttle-CMW(PSC). Pme I linearized shuttle plasmid was transformed into E.coli BJ5183-AD-1 to obtain the recombinant adenoviral plasmid pAd-mB7-H4 by efficient homologous recombination. Then the recombinant adenovirus-mB7-H4/Ad was obtained by packaging Pac I linearized in D-293 cells. The mRNA and protein expression of B7-H4 in mB7-H4/Ad infected AD-293 cells were detected by RT-PCR and Western blot, respectively. mB7-H4/Ad was used to infect L929 cells, the bioactivity of expressed B7-H4 in stimulation of T lymphocytes proliferation and cytokine production were tested. RESULTS: The full-length of mB7-H4 was cloned from mouse lung tissue cDNA and verified by sequencing. The recombinant plasmid pAd-m B7-H4 was successfully generated by homologous recombination, and the primary mB7-H4/Ad was obtained by packaging pAd-B7-H4 in AD-293 cells. Compared with the negative control, L929 cells infected with mB7-H4/Ad effectively inhibited the proliferation of T lymphocytes and cytokines production. CONCLUSION: The bioactive recombinant adenovirus mB7-H4/Ad has been successfully constructed.