Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis

• Published in: Frontiers in immunology Vol. 13; p. 828949
• Main Authors: Sehgal, Rashi, Maiwall, Rakhi, Rajan, Vijayaraghavan, Islam, Mojahidul, Baweja, Sukriti, Kaur, Navkiran, Kumar, Guresh, Ramakrishna, Gayatri, Sarin, Shiv K., Trehanpati, Nirupma
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 03.06.2022
• Subjects: GM-CSF; immune modulation; Immunology; liver cirrhosis; myeloid-derived suppressor cells; sepsis; Tregs
• DOI: 10.3389/fimmu.2022.828949
• ISSN: 1664-3224

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.