Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis
Rashi Sehgal, Rakhi Maiwall, Vijayaraghavan Rajan, Mojahidul Islam, Sukriti Baweja, Navkiran Kaur, Guresh Kumar, Gayatri Ramakrishna, Shiv Kumar Sarin, Nirupma Trehanpati
Abstract
Background Decompensated cirrhosis patients are more prone to bacterial infections. Myeloid-derived suppressor cells (MDSCs) expand in sepsis patients and disrupt immune cell functions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy helps in restoring immune cell functions and resolving infections. Its role in MDSC modulation in cirrhosis with sepsis is not well understood. Methods A total of 164 decompensated cirrhotic—62 without (w/o), 72 with sepsis, and 30 with sepsis treated with GM-CSF—and 15 healthy were studied. High-dimensional flow cytometry was performed to analyze MDSCs, monocytes, neutrophils, CD4 T cells, and Tregs at admission and on days 3 and day 7. Ex vivo co-cultured MDSCs with T cells were assessed for proliferation and apoptosis of T cells and differentiation to Tregs. Plasma factors and mRNA levels were analyzed by cytokine-bead assay and qRT-PCR. Results Frequencies of MDSCs and Tregs were significantly increased ( p = 0.011 and p = 0.02) with decreased CD4 T cells ( p = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) ( p = 0.000, p = 0.07, and p = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels ( p = 0.016, p = 0.043, and p = 0.045). Ex vivo co-cultured MDSCs with T cells drove T-cell apoptosis ( p = 0.03, p = 0.03) with decreased T-cell proliferation and enhanced FOXP3 + expression ( p = 0.044 and p = 0.043) in sepsis compared to w/o sepsis at day 0. Moreover, blocking the MDSCs with inhibitors suppressed FOXP3 expression. GM-CSF treatment in sepsis patients significantly decreased MDSCs and FOXP3 + Tregs but increased CD4 T-cell functionality and improved survival. Conclusion MDSCs have an immunosuppressive function by expanding FOXP3 + Tregs and inhibiting CD4 + T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.