Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

SOTIO a s Prague Czech Republic

Zobrazit více v PubMed

Roep BO, Tree TI. Immune modulation in humans: implications for type 1 diabetes mellitus. Nature reviews Endocrinology. 2014;10(4):229–42. 10.1038/nrendo.2014.2 PubMed DOI

Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clinical and experimental immunology. 2009;155(2):173–81. 10.1111/j.1365-2249.2008.03860.x PubMed DOI PMC

Baker PR 2nd, Steck AK. The past, present, and future of genetic associations in type 1 diabetes. Current diabetes reports. 2011;11(5):445–53. 10.1007/s11892-011-0212-0 PubMed DOI

Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature genetics. 2009;41(6):703–7. 10.1038/ng.381 PubMed DOI PMC

Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, Mychaleckyj JC, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nature genetics. 2015;47(4):381–6. 10.1038/ng.3245 PubMed DOI PMC

Bonifacio E. Predicting type 1 diabetes using biomarkers. Diabetes care. 2015;38(6):989–96. 10.2337/dc15-0101 PubMed DOI

Mantovani A. The growing diversity and spectrum of action of myeloid-derived suppressor cells. European journal of immunology. 2010;40(12):3317–20. 10.1002/eji.201041170 PubMed DOI

Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature reviews Immunology. 2009;9(3):162–74. 10.1038/nri2506 PubMed DOI PMC

Brudecki L, Ferguson DA, McCall CE, El Gazzar M. Myeloid-derived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. Infection and immunity. 2012;80(6):2026–34. 10.1128/IAI.00239-12 PubMed DOI PMC

Dilek N, Vuillefroy de Silly R, Blancho G, Vanhove B. Myeloid-derived suppressor cells: mechanisms of action and recent advances in their role in transplant tolerance. Front Immunol. 2012;3:208 10.3389/fimmu.2012.00208 PubMed DOI PMC

Dorhoi A, Du Plessis N. Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections. Front Immunol. 2017;8:1895 10.3389/fimmu.2017.01895 PubMed DOI PMC

Medina E, Hartl D. Myeloid-Derived Suppressor Cells in Infection: A General Overview. Journal of innate immunity. 2018;10(5–6):407–13. 10.1159/000489830 PubMed DOI PMC

Zhao Y, Wu T, Shao S, Shi B, Zhao Y. Phenotype, development, and biological function of myeloid-derived suppressor cells. Oncoimmunology. 2016;5(2):e1004983 10.1080/2162402X.2015.1004983 PubMed DOI PMC

Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V, et al. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry Part B, Clinical cytometry. 2015;88(2):77–91. 10.1002/cyto.b.21206 PubMed DOI PMC

Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, et al. The terminology issue for myeloid-derived suppressor cells. Cancer research. 2007;67(1):425; author reply 6. 10.1158/0008-5472.CAN-06-3037 PubMed DOI PMC

Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C, et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer immunology, immunotherapy: CII. 2016;65(2):161–9. 10.1007/s00262-015-1782-5 PubMed DOI PMC

Cassetta L, Baekkevold ES, Brandau S, Bujko A, Cassatella MA, Dorhoi A, et al. Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates. Cancer immunology, immunotherapy: CII. 2019;68(4):687–97. 10.1007/s00262-019-02302-2 PubMed DOI PMC

Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC. Regulation of T cell receptor CD3zeta chain expression by L-arginine. The Journal of biological chemistry. 2002;277(24):21123–9. 10.1074/jbc.M110675200 PubMed DOI

Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer research. 2005;65(8):3044–8. 10.1158/0008-5472.CAN-04-4505 PubMed DOI

Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. Journal of immunology. 2009;182(9):5693–701. 10.4049/jimmunol.0900092 PubMed DOI PMC

Bronte V, Mocellin S. Suppressive influences in the immune response to cancer. Journal of immunotherapy. 2009;32(1):1–11. 10.1097/CJI.0b013e3181837276 PubMed DOI

Lelis FJN, Jaufmann J, Singh A, Fromm K, Teschner AC, Poschel S, et al. Myeloid-derived suppressor cells modulate B-cell responses. Immunology letters. 2017;188:108–15. 10.1016/j.imlet.2017.07.003 PubMed DOI

Ozkan B, Lim H, Park SG. Immunomodulatory Function of Myeloid-Derived Suppressor Cells during B Cell-Mediated Immune Responses. International journal of molecular sciences. 2018;19(5). 10.3390/ijms19051468 PubMed DOI PMC

Crook KR, Jin M, Weeks MF, Rampersad RR, Baldi RM, Glekas AS, et al. Myeloid-derived suppressor cells regulate T cell and B cell responses during autoimmune disease. Journal of leukocyte biology. 2015;97(3):573–82. 10.1189/jlb.4A0314-139R PubMed DOI PMC

Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138(2):105–15. 10.1111/imm.12036 PubMed DOI PMC

Sacchi A, Tumino N, Sabatini A, Cimini E, Casetti R, Bordoni V, et al. Myeloid-Derived Suppressor Cells Specifically Suppress IFN-gamma Production and Antitumor Cytotoxic Activity of Vdelta2 T Cells. Front Immunol. 2018;9:1271 10.3389/fimmu.2018.01271 PubMed DOI PMC

Ioannou M, Alissafi T, Lazaridis I, Deraos G, Matsoukas J, Gravanis A, et al. Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. Journal of immunology. 2012;188(3):1136–46. 10.4049/jimmunol.1101816 PubMed DOI

Park MJ, Lee SH, Kim EK, Lee EJ, Baek JA, Park SH, et al. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice. Scientific reports. 2018;8(1):3753 10.1038/s41598-018-21856-2 PubMed DOI PMC

Haile LA, von Wasielewski R, Gamrekelashvili J, Kruger C, Bachmann O, Westendorf AM, et al. Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology. 2008;135(3):871–81, 81 e1-5. 10.1053/j.gastro.2008.06.032 PubMed DOI

Marhaba R, Vitacolonna M, Hildebrand D, Baniyash M, Freyschmidt-Paul P, Zoller M. The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. Journal of immunology. 2007;179(8):5071–81. 10.4049/jimmunol.179.8.5071 PubMed DOI

Ji J, Xu J, Zhao S, Liu F, Qi J, Song Y, et al. Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs. Clinical science. 2016;130(16):1453–67. 10.1042/CS20160311 PubMed DOI

Jiao Z, Hua S, Wang W, Wang H, Gao J, Wang X. Increased circulating myeloid-derived suppressor cells correlated negatively with Th17 cells in patients with rheumatoid arthritis. Scandinavian journal of rheumatology. 2013;42(2):85–90. 10.3109/03009742.2012.716450 PubMed DOI

Kurko J, Vida A, Glant TT, Scanzello CR, Katz RS, Nair A, et al. Identification of myeloid-derived suppressor cells in the synovial fluid of patients with rheumatoid arthritis: a pilot study. BMC musculoskeletal disorders. 2014;15:281 10.1186/1471-2474-15-281 PubMed DOI PMC

Zhang H, Wang S, Huang Y, Wang H, Zhao J, Gaskin F, et al. Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clinical immunology. 2015;157(2):175–86. 10.1016/j.clim.2015.02.001 PubMed DOI PMC

Yin B, Ma G, Yen CY, Zhou Z, Wang GX, Divino CM, et al. Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. Journal of immunology. 2010;185(10):5828–34. 10.4049/jimmunol.0903636 PubMed DOI PMC

Whitfield-Larry F, Felton J, Buse J, Su MA. Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients. Clinical immunology. 2014;153(1):156–64. 10.1016/j.clim.2014.04.006 PubMed DOI

Cinek O, Kolouskova S, Snajderova M, Sumnik Z, Sedlakova P, Drevinek P, et al. HLA class II genetic association of type 1 diabetes mellitus in Czech children. Pediatric diabetes. 2001;2(3):98–102. 10.1034/j.1399-5448.2001.002003098.x PubMed DOI

12. Children and Adolescents: Standards of Medical Care in Diabetes—2018. Diabetes care. 2018;41(Supplement 1):S126–S36. 10.2337/dc18-S012 PubMed DOI

Danova K, Grohova A, Strnadova P, Funda DP, Sumnik Z, Lebl J, et al. Tolerogenic Dendritic Cells from Poorly Compensated Type 1 Diabetes Patients Have Decreased Ability To Induce Stable Antigen-Specific T Cell Hyporesponsiveness and Generation of Suppressive Regulatory T Cells. Journal of immunology. 2017;198(2):729–40. 10.4049/jimmunol.1600676 PubMed DOI

Grohová A, Dáňová K, Špíšek R, Palová-Jelínková L. Cell Based Therapy for Type 1 Diabetes: Should We Take Hyperglycemia Into Account? Frontiers in Immunology. 2019;10(79). 10.3389/fimmu.2019.00079 PubMed DOI PMC

Lu H, Yao K, Huang D, Sun A, Zou Y, Qian J, et al. High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells. Cardiovascular diabetology. 2013;12:80 10.1186/1475-2840-12-80 PubMed DOI PMC

Kumar P, Natarajan K, Shanmugam N. High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. Cellular signalling. 2014;26(3):528–39. 10.1016/j.cellsig.2013.11.031 PubMed DOI

Han XQ, Gong ZJ, Xu SQ, Li X, Wang LK, Wu SM, et al. Advanced glycation end products promote differentiation of CD4(+) T helper cells toward pro-inflammatory response. Journal of Huazhong University of Science and Technology Medical sciences = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban. 2014;34(1):10–7. 10.1007/s11596-014-1224-1 PubMed DOI

Kuriya G, Uchida T, Akazawa S, Kobayashi M, Nakamura K, Satoh T, et al. Double deficiency in IL-17 and IFN-gamma signalling significantly suppresses the development of diabetes in the NOD mouse. Diabetologia. 2013;56(8):1773–80. 10.1007/s00125-013-2935-8 PubMed DOI

Li Y, Liu Y, Chu CQ. Th17 Cells in Type 1 Diabetes: Role in the Pathogenesis and Regulation by Gut Microbiome. Mediators of inflammation. 2015;2015:638470 10.1155/2015/638470 PubMed DOI PMC

Reinert-Hartwall L, Honkanen J, Salo HM, Nieminen JK, Luopajarvi K, Harkonen T, et al. Th1/Th17 plasticity is a marker of advanced beta cell autoimmunity and impaired glucose tolerance in humans. Journal of immunology. 2015;194(1):68–75. 10.4049/jimmunol.1401653 PubMed DOI PMC

Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends in immunology. 2016;37(3):208–20. 10.1016/j.it.2016.01.004 PubMed DOI PMC

Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. The Journal of clinical investigation. 2015;125(9):3356–64. 10.1172/JCI80005 PubMed DOI PMC

Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer immunology research. 2017;5(1):3–8. 10.1158/2326-6066.CIR-16-0297 PubMed DOI PMC

Fujimura T, Kambayashi Y, Aiba S. Crosstalk between regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) during melanoma growth. Oncoimmunology. 2012;1(8):1433–4. 10.4161/onci.21176 PubMed DOI PMC

Paluskievicz CM, Cao X, Abdi R, Zheng P, Liu Y, Bromberg JS. T Regulatory Cells and Priming the Suppressive Tumor Microenvironment. Front Immunol. 2019;10:2453 10.3389/fimmu.2019.02453 PubMed DOI PMC

Hu C, Du W, Zhang X, Wong FS, Wen L. The role of Gr1+ cells after anti-CD20 treatment in type 1 diabetes in nonobese diabetic mice. Journal of immunology. 2012;188(1):294–301. 10.4049/jimmunol.1101590 PubMed DOI PMC

Fu W, Wojtkiewicz G, Weissleder R, Benoist C, Mathis D. Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging. Nature immunology. 2012;13(4):361–8. 10.1038/ni.2233 PubMed DOI PMC

Campbell IL, Kay TW, Oxbrow L, Harrison LC. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. The Journal of clinical investigation. 1991;87(2):739–42. 10.1172/JCI115055 PubMed DOI PMC

Fatima N, Faisal SM, Zubair S, Ajmal M, Siddiqui SS, Moin S, et al. Role of Pro-Inflammatory Cytokines and Biochemical Markers in the Pathogenesis of Type 1 Diabetes: Correlation with Age and Glycemic Condition in Diabetic Human Subjects. PloS one. 2016;11(8):e0161548 10.1371/journal.pone.0161548 PubMed DOI PMC

Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. The Journal of clinical investigation. 2002;110(6):851–60. 10.1172/JCI15318 PubMed DOI PMC

Dogan Y, Akarsu S, Ustundag B, Yilmaz E, Gurgoze MK. Serum IL-1beta, IL-2, and IL-6 in insulin-dependent diabetic children. Mediators of inflammation. 2006;2006(1):59206 10.1155/MI/2006/59206 PubMed DOI PMC

Stechova K, Bohmova K, Vrabelova Z, Sepa A, Stadlerova G, Zacharovova K, et al. High T-helper-1 cytokines but low T-helper-3 cytokines, inflammatory cytokines and chemokines in children with high risk of developing type 1 diabetes. Diabetes/metabolism research and reviews. 2007;23(6):462–71. 10.1002/dmrr.718 PubMed DOI

Xi Q, Li Y, Dai J, Chen W. High frequency of mononuclear myeloid-derived suppressor cells is associated with exacerbation of inflammatory bowel disease. Immunological investigations. 2015;44(3):279–87. 10.3109/08820139.2014.999937 PubMed DOI

Cao LY, Chung JS, Teshima T, Feigenbaum L, Cruz PD Jr, Jacobe HT, et al. Myeloid-Derived Suppressor Cells in Psoriasis Are an Expanded Population Exhibiting Diverse T-Cell-Suppressor Mechanisms. The Journal of investigative dermatology. 2016;136(9):1801–10. 10.1016/j.jid.2016.02.816 PubMed DOI PMC

Ilkovitch D, Ferris LK. Myeloid-derived suppressor cells are elevated in patients with psoriasis and produce various molecules. Molecular medicine reports. 2016;14(4):3935–40. 10.3892/mmr.2016.5685 PubMed DOI PMC

Leclerc E, Fritz G, Vetter SW, Heizmann CW. Binding of S100 proteins to RAGE: an update. Biochimica et biophysica acta. 2009;1793(6):993–1007. 10.1016/j.bbamcr.2008.11.016 PubMed DOI

Huang M, Wu R, Chen L, Peng Q, Li S, Zhang Y, et al. S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma. Front Immunol. 2019;10:2243 10.3389/fimmu.2019.02243 PubMed DOI PMC

Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. Journal of immunology. 2008;181(7):4666–75. 10.4049/jimmunol.181.7.4666 PubMed DOI PMC

Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J, et al. TNF signaling drives myeloid-derived suppressor cell accumulation. The Journal of clinical investigation. 2012;122(11):4094–104. 10.1172/JCI64115 PubMed DOI PMC

Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M. Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity. 2013;38(3):541–54. 10.1016/j.immuni.2013.02.007 PubMed DOI

Qiao YC, Chen YL, Pan YH, Tian F, Xu Y, Zhang XX, et al. The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis. PloS one. 2017;12(4):e0176157 10.1371/journal.pone.0176157 PubMed DOI PMC

Kim J, Kang S, Kim J, Kwon G, Koo S. Elevated levels of T helper 17 cells are associated with disease activity in patients with rheumatoid arthritis. Annals of laboratory medicine. 2013;33(1):52–9. 10.3343/alm.2013.33.1.52 PubMed DOI PMC

Zhang L, Zhang Z, Zhang H, Wu M, Wang Y. Myeloid-derived suppressor cells protect mouse models from autoimmune arthritis via controlling inflammatory response. Inflammation. 2014;37(3):670–7. 10.1007/s10753-013-9783-z PubMed DOI

Fujii W, Ashihara E, Hirai H, Nagahara H, Kajitani N, Fujioka K, et al. Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis. Journal of immunology. 2013;191(3):1073–81. 10.4049/jimmunol.1203535 PubMed DOI

Wen L, Gong P, Liang C, Shou D, Liu B, Chen Y, et al. Interplay between myeloid-derived suppressor cells (MDSCs) and Th17 cells: foe or friend? Oncotarget. 2016;7(23):35490–6. 10.18632/oncotarget.8204 PubMed DOI PMC

Guo C, Hu F, Yi H, Feng Z, Li C, Shi L, et al. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Annals of the rheumatic diseases. 2016;75(1):278–85. 10.1136/annrheumdis-2014-205508 PubMed DOI PMC

Li M, Zhu D, Wang T, Xia X, Tian J, Wang S. Roles of Myeloid-Derived Suppressor Cell Subpopulations in Autoimmune Arthritis. Front Immunol. 2018;9:2849 10.3389/fimmu.2018.02849 PubMed DOI PMC

Yi H, Guo C, Yu X, Zuo D, Wang XY. Mouse CD11b+Gr-1+ myeloid cells can promote Th17 cell differentiation and experimental autoimmune encephalomyelitis. Journal of immunology. 2012;189(9):4295–304. 10.4049/jimmunol.1200086 PubMed DOI PMC

Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, et al. Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. The Journal of experimental medicine. 2013;210(7):1433–445. 10.1084/jem.20121277 PubMed DOI PMC

Novitskiy SV, Pickup MW, Gorska AE, Owens P, Chytil A, Aakre M, et al. TGF-beta receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Cancer discovery. 2011;1(5):430–41. 10.1158/2159-8290.CD-11-0100 PubMed DOI PMC

He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. Journal of immunology. 2010;184(5):2281–8. 10.4049/jimmunol.0902574 PubMed DOI PMC

Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer research. 2006;66(2):1123–31. 10.1158/0008-5472.CAN-05-1299 PubMed DOI

Cripps JG, Wang J, Maria A, Blumenthal I, Gorham JD. Type 1 T helper cells induce the accumulation of myeloid-derived suppressor cells in the inflamed Tgfb1 knockout mouse liver. Hepatology. 2010;52(4):1350–9. 10.1002/hep.23841 PubMed DOI PMC

Rodriguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunological reviews. 2008;222:180–91. 10.1111/j.1600-065X.2008.00608.x PubMed DOI PMC

Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nature reviews Immunology. 2005;5(8):641–54. 10.1038/nri1668 PubMed DOI

Bian Z, Abdelaal AM, Shi L, Liang H, Xiong L, Kidder K, et al. Arginase-1 is neither constitutively expressed in nor required for myeloid-derived suppressor cell-mediated inhibition of T-cell proliferation. European journal of immunology. 2018;48(6):1046–58. 10.1002/eji.201747355 PubMed DOI PMC

Bauswein M, Singh A, Ralhan A, Neri D, Fuchs K, Blanz KD, et al. Human T cells modulate myeloid-derived suppressor cells through a TNF-alpha-mediated mechanism. Immunology letters. 2018;202:31–7. 10.1016/j.imlet.2018.07.010 PubMed DOI

Ersek B, Molnar V, Balogh A, Matko J, Cope AP, Buzas EI, et al. CD3zeta-chain expression of human T lymphocytes is regulated by TNF via Src-like adaptor protein-dependent proteasomal degradation. Journal of immunology. 2012;189(4):1602–10. PubMed

Myers MD, Sosinowski T, Dragone LL, White C, Band H, Gu H, et al. Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex. Nature immunology. 2006;7(1):57–66. 10.1038/ni1291 PubMed DOI