Myeloid-derived suppressor cells suppress CD4+ and CD8+ T cell responses in autoimmune hepatitis

Li,Haiwen; Dai,Fu; Peng,Qiong; Gan,Huizhong; Zheng,Jishun; Xia,Yunling; Zhang,Wanyuan

doi:10.3892/mmr.2015.3791

Myeloid-derived suppressor cells suppress CD4+ and CD8+ T cell responses in autoimmune hepatitis

Authors:
- Haiwen Li
- Fu Dai
- Qiong Peng
- Huizhong Gan
- Jishun Zheng
- Yunling Xia
- Wanyuan Zhang
View Affiliations

Affiliations: Department of Gastroenterology, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P.R. China
Published online on: May 15, 2015 https://doi.org/10.3892/mmr.2015.3791
Pages: 3667-3673

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Myeloid-derived suppressor cells (MDSCs) have been demonstrated with possess the ability to suppress T‑cell responses. Therefore, MDSCs are an attractive candidate for immune intervention aimed at reconstituting self‑tolerance in autoimmune conditions. The present study investigated the frequency and function of MDSCs in the peripheral blood of patients with autoimmune hepatitis (AIH), and examined its correlation with disease progression. Peripheral blood samples were obtained from 48 patients diagnosed with AIH and 24 healthy controls. The frequency of MDSCs was analyzed using flow cytometry, and its correlation with liver biochemical indicators was assessed. The sorted peripheral blood mononuclear cells and MDSCs, cocultivated with CD3 and CD28 monoclonal antibodies, were labeled with carboxylfluorescein succinimidyl ester and detected using flow cytometry for the proliferation of T cells. T cell apoptosis was detected using annexin V and 7‑aminoactinomycin D. Interferon γ and nitric oxide were detected using ELISA, and inducible nitric oxide synthase (iNOS) was detected using immunohistochemical staining. The frequency of MDSCs in the patients with non‑cirrhotic AIH was significantly higher, compared with the healthy controls and patients with cirrhotic AIH (P<0.05). However, no significantly differences were observed between the patients with cirrhotic AIH and the healthy controls (P>0.05). In addition, the frequency of MDSCs in the peripheral blood was positively correlated with alanine transaminase and aspartate transaminase in patients with AIH. The T cells of the incubation system were suppressed by the MDSCs, which was associated with the iNOS expressed on MDSCs. In patients with non‑cirrhotic AIH, the peripheral frequency of MDSCs was increased through a feedback loop and autoimmune responses were inhibited. However, a variety of causes led to a decrease in the number of MDSCs in patients with cirrhotic AIH, therefore, accelerating the progression of liver injury and liver cirrhosis.

View Figures

View References

1	Manns MP and Vogel A: Autoimmune hepatitis, from mechanisms to therapy. Hepatology. 43(Suppl 2): 132–144. 2006. View Article : Google Scholar
2	Longhi MS, Ma Y, Mieli Vergani G and Vergani D: Aetiopathogenesis of autoimmune hepatitis. J autoimmun. 34:7–14. 2010. View Article : Google Scholar
3	Longhi MS, Meda F, Wang P, Samyn M, Mieli-Vergani G, Vergani D and Ma Y: Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis. Hepatology. 47:581–591. 2008. View Article : Google Scholar : PubMed/NCBI
4	Kawamura H, Aswad F, Minagawa M, Govindarajan S and Dennert G: P2X7 receptors regulate NKT cells in autoimmune hepatitis. J Immunol. 176:2152–2160. 2006. View Article : Google Scholar : PubMed/NCBI
5	Gabrilovich DI and Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174. 2009. View Article : Google Scholar : PubMed/NCBI
6	Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S and Bronte V: Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol. 22:238–244. 2010. View Article : Google Scholar : PubMed/NCBI
7	Solito S, Falisi E, Diaz-Montero CM, Doni A, et al: A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood. 118:2254–2265. 2011. View Article : Google Scholar : PubMed/NCBI
8	Haile LA, von Wasielewski R, Gamrekelashvili J, Krüger C, Bachmann O, Westendorf AM, et al: Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology. 135:871–881. 881e1–e5. 2008. View Article : Google Scholar : PubMed/NCBI
9	Goh C, Narayanan S and Hahn YS: Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev. 255:210–221. 2013. View Article : Google Scholar : PubMed/NCBI
10	Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N, et al: Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol. 9:470–481. 2009. View Article : Google Scholar : PubMed/NCBI
11	Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D and Vierling JM: Diagnosis and management of autoimmune hepatitis. Hepatology. 51:2193–2213. 2010. View Article : Google Scholar : PubMed/NCBI
12	Monu NR and Frey AB: Myeloid-derived suppressor cells and anti-tumor T cells: A complex relationship. Immunol Invest. 41:595–613. 2012. View Article : Google Scholar : PubMed/NCBI
13	Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, et al: Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood. 116:5738–5747. 2010. View Article : Google Scholar : PubMed/NCBI
14	Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T and Epstein AL: Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. J Transl Med. 9:902011. View Article : Google Scholar : PubMed/NCBI
15	Goedegebuure P, Mitchem JB, Porembka MR, Tan MC, Belt BA, Wang-Gillam A, et al: Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer. Curr Cancer Drug Targets. 11:734–751. 2011. View Article : Google Scholar : PubMed/NCBI
16	Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, et al: A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 135:234–243. 2008. View Article : Google Scholar : PubMed/NCBI
17	Liu CY, Wang YM, Wang CL, Feng PH, Ko HW, Liu YH, et al: Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14 (-)/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol. 136:35–45. 2010. View Article : Google Scholar
18	Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, et al: Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol. 188:5365–5376. 2012. View Article : Google Scholar : PubMed/NCBI
19	Raber PL, Thevenot P, Sierra R, et al: Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways. Int J Cancer. 134:2853–2864. 2014. View Article : Google Scholar :
20	Jia W, Jackson-Cook C and Graf MR: Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma+vaccination model. J Neuroimmunol. 223:20–30. 2010. View Article : Google Scholar : PubMed/NCBI
21	Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, et al: Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest. 121:4015–4029. 2011. View Article : Google Scholar : PubMed/NCBI
22	Lechner MG, Liebertz DJ and Epstein AL: Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol. 185:2273–2284. 2010. View Article : Google Scholar : PubMed/NCBI
23	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. J Immunol. 188:1136–1146. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kerr EC, Raveney BJ, Copland DA, Dick AD and Nicholson LB: Analysis of retinal cellular infiltrate in experimental autoimmune uveoretinitis reveals multiple regulatory cell populations. J Autoimmun. 31:354–361. 2008. View Article : Google Scholar : PubMed/NCBI
25	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. J Immunol. 185:5828–5834. 2010. View Article : Google Scholar : PubMed/NCBI
26	Carambia A and Herkel J: CD4 T cells in hepatic immune tolerance. J Autoimmun. 34:23–28. 2010. View Article : Google Scholar
27	Ribechini E, Greifenberg V, Sandwick S and Lutz MB: Subsets, expansion and activation of myeloid-derived suppressor cells. Med Microbiol Immunol. 199:273–281. 2010. View Article : Google Scholar : PubMed/NCBI
28	He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD and Xu H: IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol. 184:2281–2288. 2010. View Article : Google Scholar : PubMed/NCBI