Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-β-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25-FoxP3- T cells.
MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined. Previous reports have suggested that MDSC may contribute to Treg induction in cancer. Herein, we provide evidence that tumor-induced gr-MDSCs, endowed with the potential of suppressing conventional T Lc, surprisingly impair TGF-β1-mediated generation of CD4(+)CD25(+)FoxP3(+) iTregs. Furthermore, gr-MDSCs impede the proliferation of nTregs without, however, affecting FoxP3 expression. Suppression of iTreg differentiation from naïve CD4(+) cells by gr-MDSC occurs early in the polarization process, requires inhibition of early T cell activation, and depends on ROS and IDO but does not require arginase 1, iNOS, NO, cystine/cysteine depletion, PD-1 and PD-L1 signaling, or COX-2. These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs.
Department of Pediatrics, College of Medicine, University of Arizona, Tucson, AZ 85724-5073, USA.
Sara M
SM
Centuori
Malika
M
Trad
Collin J
CJ
LaCasse
Darya
D
Alizadeh
Claire B
CB
Larmonier
Neale T
NT
Hanke
Jessica
J
Kartchner
Nona
N
Janikashvili
Bernard
B
Bonnotte
Nicolas
N
Larmonier
Emmanuel
E
Katsanis
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta