ER Stress Regulates Immunosuppressive Function of Myeloid Derived Suppressor Cells in Leprosy that Can Be Overcome in the Presence of IFN-γ
Kindra M. Kelly-Scumpia,
Aaron Choi,
Roksana Shirazi,
Hannah Bersabe,
Esther Park,
Philip O. Scumpia,
Maria T. Ochoa,
Jing Yu,
Feiyang Ma,
Matteo Pellegrini,
Robert L. Modlin
Affiliations
Kindra M. Kelly-Scumpia
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Corresponding author
Aaron Choi
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Roksana Shirazi
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Hannah Bersabe
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Esther Park
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Philip O. Scumpia
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Maria T. Ochoa
Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
Jing Yu
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Feiyang Ma
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Matteo Pellegrini
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Robert L. Modlin
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
Summary: Myeloid derived suppressor cells (MDSCs) are a population of immature myeloid cells that suppress adaptive immune function, yet the factors that regulate their suppressive function in patients with infection remain unclear. We studied MDSCs in patients with leprosy, a disease caused by Mycobacterium leprae, where clinical manifestations present on a spectrum that correlate with immunity to the pathogen. We found that HLA-DR-CD33+CD15+ MDSCs were increased in blood from patients with disseminated/progressive lepromatous leprosy and possessed T cell-suppressive activity as compared with self-limiting tuberculoid leprosy. Mechanistically, we found ER stress played a critical role in regulating the T cell suppressive activity in these MDSCs. Furthermore, ER stress augmented IL-10 production, contributing to MDSC activity, whereas IFN-γ allowed T cells to overcome MDSC suppressive activity. These studies highlight a regulatory mechanism that links ER stress to IL-10 in mediating MDSC suppressive function in human infectious disease.
