Type 1 T helper cells induce the accumulation of myeloid-derived suppressor cells in the inflamed Tgfb1 knockout mouse liver.
Immune-mediated liver injury in hepatitis is due to activated T cells producing interferon-γ (IFN-γ). It is important to identify negative feedback immune mechanisms that can regulate T cell activity. In this study, we demonstrate that liver inflammation mediated by type 1 T helper (Th1) cells can induce the accumulation of myeloid-derived suppressor cells (MDSCs), pleiomorphic cells capable of modulating T cell-mediated immunity, that heretofore have been studied almost exclusively in the context of tumor-associated inflammation. Mice deficient in the gene encoding transforming growth factor-β1 (Tgfb1(-/-) mice) acutely develop liver necroinflammation caused by IFN-γ-producing clusters of differentiation 4-positive (CD4(+)) T cells. Liver Th1 cell accumulation was accompanied by myeloid cells expressing CD11b and Gr1, phenotypic hallmarks of MDSCs. Isolated Tgfb1(-/-) liver CD11b(+)Gr1(+) cells were functional MDSCs, readily suppressing T cell proliferation in vitro. Pharmacologic inhibitors of inducible nitric oxide (NO) synthase completely eliminated suppressor function. Suppressor function and the production of NO were dependent on cell-cell contact between MDSCs and T cells, and upon IFN-γ, and were specifically associated with the "monocytic" CD11b(+)Ly6G(-) Ly6C(hi) subset of liver Tgfb1(-/-) CD11b(+) cells. The rapid accumulation of CD11b(+)Gr1(+) cells in Tgfb1(-/-) liver was abrogated when mice were either depleted of CD4(+) T cells or rendered unable to produce IFN-γ, showing that Th1 activity induces MDSC accumulation.


CONCLUSIONS
Th1 liver inflammation mobilizes an MDSC response that, through the production of NO, can inhibit T cell proliferation. We propose that MDSCs serve an important negative feedback function in liver immune homeostasis, and that insufficient or inappropriate activity of this cell population may contribute to inflammatory liver pathology.
Cripps
James G
JG
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Wang
Jing
J
Maria
Ann
A
Blumenthal
Ian
I
Gorham
James D
JD
D000818:Animals; D039481:CD11b Antigen / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D049109:Cell Proliferation / Q000187:drug effects; D006505:Hepatitis / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology*; D008099:Liver / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology; D023461:Myeloid Progenitor Cells / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D019707:Receptors, Chemokine / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D007371:Interferon-gamma
Methods Mol Biol. 1998;100:83-91
10906996
Cancer Res. 2007 Oct 15;67(20):10019-26
17942936
Cancer Res. 2009 Jul 1;69(13):5514-21
19549903
J Clin Invest. 1999 Sep;104(6):777-85
10491413
Liver Int. 2009 Oct;29(9):1307-15
19490417
J Immunol. 1993 Sep 1;151(5):2399-408
8360469
Hepatology. 1996 Oct;24(4):759-65
8855173
J Gastroenterol. 2001 Aug;36(8):544-51
11519833
Hepatology. 2009 Jul;50(1):130-42
19437492
J Immunol. 2003 May 1;170(9):4785-92
12707360
J Immunol. 2008 Oct 1;181(7):4666-75
18802069
Gastroenterology. 1996 Aug;111(2):462-71
8690213
J Immunol. 2006 Jan 1;176(1):284-90
16365420
Cancer Cell. 2008 Nov 4;14(5):408-19
18977329
Lab Invest. 2005 Apr;85(4):550-61
15696185
Cancer Lett. 2007 Jul 8;252(1):86-92
17257744
J Immunol. 2002 Jan 15;168(2):689-95
11777962
J Immunol. 2008 Oct 15;181(8):5791-802
18832739
J Exp Med. 2008 Sep 29;205(10):2235-49
18809714
Liver Transpl. 2003 Nov;9(11):S35-43
14586893
Neoplasia. 2009 Jun;11(6):564-73, 1 p following 573
19484145
Nat Rev Immunol. 2009 Mar;9(3):162-74
19197294
Hepatology. 2007 Aug;46(2):472-84
17559153
Annu Rev Immunol. 2009;27:451-83
19105661
J Immunol. 2009 Apr 15;182(8):4499-506
19342621
J Immunol. 2000 Mar 1;164(5):2585-91
10679097
Arch Dis Child. 1992 Dec;67(12):1447-53
1489223
Annu Rev Immunol. 2009;27:147-63
19302037
Liver. 1994 Jun;14(3):161-6
8078396
Clin Exp Immunol. 1993 Oct;94(1):168-73
8403501
Hepatology. 2009 Sep;50(3):799-807
19551844
J Immunol. 2001 May 15;166(10):6413-22
11342667
J Clin Invest. 2006 Oct;116(10):2777-90
17016559
PLoS Pathog. 2009 Apr;5(4):e1000371
19360123
Gastroenterology. 2008 Jul;135(1):234-43
18485901
J Immunol. 2009 Mar 1;182(5):3278-84
19234226