Project description:The tumoricidal effects of CD8+T cells are well acknowledged, but how MHC Ib-restricted CD8+T (Ib-CD8+T) cells contribute to anti-tumor immunity remains obscure. Here, we show that infusion of MHC Ia+ cells to Kb-/-Db-/- mice induced the expansion of Ib-CD8+T cells in tumors and potently inhibited tumor progression. Such priming of Ib-CD8+T cells by MHC-Ia is not MHC haplotype restricted and MHC Ia tetramers alone can prime Ib-CD8+T cells for activation. The MHC Ia priming promoted Tbet expression in Ib-CD8+T cells and in absence of Tbet, such priming effect diminished. Importantly, these tumoricidal Ib-CD8+T cells are positive for CX3CR1, and exhibit rapid proliferation, high expression of cytotoxic factors, and prolonged persistence at tumor sites. Adoptive transfer of CX3CR1+Ib-CD8+T cells to wild type mice resulted in potent anti-tumor effects. Our findings unravel an uncharacterized function of MHC Ia molecules in immunoregulation and raise the possibility of using Ib-CD8+T cells in tumor immunotherapy.
Project description:Background: Glycogen Storage Disease (GSD) Type Ia and Ib are rare metabolic diseases caused by gene variants in G6PC and SLC37A4 respectively. Patients often suffer from multiple metabolic abnormalities and severe long-term complications. Methods: In this study, we employed comprehensive untargeted proteomics on retrospectively registered samples: 26 serum/plasma samples (18 GSD Ia and 8 GSD Ib) from patients with 21 matched healthy controls, complemented by 4 liver samples from 3 patients who received liver transplantation (3 from GSD Ia including 1 with hepatocellular carcinoma tissue and 1 from GSD Ib), compared to 10 donor liver samples, to investigate the pathological mechanisms of disease complications and identify potential biomarkers. Results: Pathway analysis of the differentially regulated proteins revealed distinct changes in the serum/plasma of GSD Ia and Ib. Coagulation was the most significantly changed biological process in the GSD Ia patients. Immune response-associated proteins, especially a large number of immunoglobulins, increased in GSD Ib specifically. Proteins related to liver injury, cholesterol, and amyloidosis were altered in two subtypes, though more pronounced in GSD Ia. Potential biomarkers with significant alterations both in the circulation as well as in the liver were identified specifically for monitoring and prognosing GSD Ia (COL163 and PROC), GSD Ib (F11 and CD163), and hepatocellular carcinoma (HCC) in GSD Ia patients (ALDOB and CFHR5). Conclusions: These findings provide new insights into the pathogenesis of GSD I-related complications and highlighted the potential of protein circulating biomarkers for monitoring complication progression in GSD Ia and Ib, as well as for assessing HCC risk in GSD Ia patients.
Project description:The human-derived serotype Ⅴ ST1 GBS strains NNA038 and NNA048 was isolated from a amniotic fluid of full-term pregnant woman who suffered from premature rupture of membrane in China.Serotype Ia ST7 GBS strain YM001 is an attenuated strain ,its parent strain HN016 was isolated from an outbreak epidemical disease in tilapia from China.HN016_KO_D2 is a knockout strain from Serotype Ia ST7 GBS strain HN016.
