AUTHOR=Sehgal Rashi , Maiwall Rakhi , Rajan Vijayaraghavan , Islam Mojahidul , Baweja Sukriti , Kaur Navkiran , Kumar Guresh , Ramakrishna Gayatri , Sarin Shiv K. , Trehanpati Nirupma 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.828949

DOI=10.3389/fimmu.2022.828949

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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. <italic>Ex vivo</italic> 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.</p></sec><sec><title>Results</title><p>Frequencies of MDSCs and Tregs were significantly increased (<italic>p</italic> = 0.011 and <italic>p</italic> = 0.02) with decreased CD4 T cells (<italic>p</italic> = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) (<italic>p</italic> = 0.000, <italic>p</italic> = 0.07, and <italic>p</italic> = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels (<italic>p</italic> = 0.016, <italic>p</italic> = 0.043, and <italic>p</italic> = 0.045). <italic>Ex vivo</italic> co-cultured MDSCs with T cells drove T-cell apoptosis (<italic>p</italic> = 0.03, <italic>p</italic> = 0.03) with decreased T-cell proliferation and enhanced FOXP3<sup>+</sup> expression (<italic>p</italic> = 0.044 and <italic>p</italic> = 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<sup>+</sup> Tregs but increased CD4 T-cell functionality and improved survival.</p></sec><sec><title>Conclusion</title><p>MDSCs have an immunosuppressive function by expanding FOXP3<sup>+</sup> Tregs and inhibiting CD4<sup>+</sup> T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.</p></sec>