title: Antigen-specific CD4(+) T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling.
abstract: Myeloid-derived suppressor cells (MDSC) play a major role in cancer-related immune suppression, yet the nature of this suppression remains controversial. In this study, we evaluated the ability of MDSCs to elicit CD4(+) T-cell tolerance in different mouse tumor models. In contrast to CD8(+) T-cell tolerance, which could be induced by MDSCs in all the tumor models tested, CD4(+) T-cell tolerance could be elicited in only one of the models (MC38) in which a substantial level of MHC class II was expressed on MDSCs compared with control myeloid cells. Mechanistic investigations revealed that MDSCs deficient in MHC class II could induce tolerance to CD8(+) T cells but not to CD4(+) T cells. Unexpectedly, antigen-specific CD4(+) T cells (but not CD8(+) T cells) could dramatically enhance the immune suppressive activity of MDSCs by converting them into powerful nonspecific suppressor cells. This striking effect was mediated by direct cell-cell contact through cross-linking of MHC class II on MDSCs. We also implicated an Ets-1 transcription factor-regulated increase in expression of Cox-2 and prostaglandin E2 in MDSCs in mediating this effect. Together, our findings suggest that activated CD4(+) T cells that are antigen specific may enhance the immune suppressive activity of MDSCs, a mechanism that might serve normally as a negative feedback loop to control immune responses that becomes dysregulated in cancer.
authors.affiliation: Department of Internal Medicine, University of South Florida, Tampa, Florida 33612, USA. snagaraj@health.usf.edu
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nagaraj
authors.forename: Allison
authors.initials: A
authors.lastname: Nelson
authors.forename: Je-in
authors.initials: JI
authors.lastname: Youn
authors.forename: Pingyan
authors.initials: P
authors.lastname: Cheng
authors.forename: David
authors.initials: D
authors.lastname: Quiceno
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000939:Epitopes; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000939:Epitopes; D000949:Histocompatibility Antigens Class II