A variety of liver resident cells participate in the regulation of T cells, including regulatory T cells, dendritic cells, see more Kupffer cells, natural killer
cells, natural killer T cells, stellate cells, and liver sinusoidal epithelial cells.10 Whether regulatory immunocytes accumulate in liver in response to activated T cells is not known. Such cells may represent an important negative feedback mechanism mitigating pathology mediated by T cell activation. It is reasonable to postulate that inflammatory pathology in liver is attributable both to aberrant activation of T cells and to a deficit in appropriate counter-regulatory mechanisms. Studies emerging from the field of tumor immunity show that tumor-associated inflammation induces the development and accumulation of myeloid-lineage cells with immunomodulatory activity. Termed myeloid-derived suppressor cells (MDSCs), these pleiomorphic cells are capable
of suppressing T cell proliferation and subjugating T cell–mediated immunity.11, 12 MDSCs comprise a heterogeneous group of myeloid cells, which employ a variety of mechanisms to inhibit T cell responses. Murine MDSCs are operationally defined as CD11b+Gr1+ myeloid cells that suppress T cell proliferation.11, 12 Although MDSCs have been most extensively described in the context of tumors, recent studies show their involvement in inflammatory responses not associated with tumors.13, 14 MDSCs home to liver in tumor-bearing mice,15 Selleck CT99021 and hepatocellular carcinoma, like other solid tumors, exhibits associated populations of MDSCs,16, 17 but little is otherwise known about MDSCs in liver, particularly in inflammatory pathology.
Here, we demonstrate in the BALB/c TGF-β1 knockout mouse model that Th1 cells, through release of IFN-γ, drive accumulation in liver of an MDSC population that can effectively inhibit T cell proliferation through a mechanism involving expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO). AIH, autoimmune hepatitis; CCL2, chemokine (C-C motif) ligand 2; CCR2, chemokine (C-C FER motif) receptor 2; CD, clusters of differentiation; CFSE,5-(and-6)- carboxyfluorescein diacetate, succinimidyl ester; D-NMMA, D-NG- monomethyl arginine citrate; IL, interleukin; iNOS, inducible nitric oxide synthase; L-NIL, N6-(1-iminoethyl)-L-lysine; L-NMMA, L-NG- monomethyl arginine citrate; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; NO, nitric oxide; nor-NOHA, N- hydroxy-nor-arginine; TCR, T cell receptor; Th1, type 1 T helper cell. Mice were bred at Dartmouth Medical School according to Association for Assessment and Accreditation of Laboratory Animal Care practices. BALB/c-background Tgfb1−/− mice, Ifng−/− (null for IFN-γ gene) Tgfb1−/− mice, and Rag1−/− (null for recombination activating gene 1) Tgfb1−/− mice were genotyped as described.