Intrahepatic IL-10 Maintains NKG2A+Ly49- Liver NK Cells in a Functionally Hyporesponsive State

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2010 Feb 4

PMID 20124099

Citations 75

Authors

Matthew G Lassen

John R Lukens

Joseph S Dolina

Michael G Brown

Young S Hahn

Affiliations

Soon will be listed here.

Abstract

The tolerogenic nature of the liver allows daily exposure to gut-derived foreign Ags without causing inflammation, but it may facilitate persistent infection in the liver. NK cells play a central role in innate immunity, as well as in shaping the adaptive immune response. We hypothesized that the naive mouse liver maintains intrahepatic NK cells in a functionally hyporesponsive state. Compared with splenic NK cells, liver NK cells displayed a dampened IFN-gamma response to IL-12/IL-18 stimulation. Importantly, the liver contains a significant population of functionally hyporesponsive NK cells that express high levels of the inhibitory receptor NKG2A and lack expression of MHC class I-binding Ly49 receptors. Adoptively transferred splenic NK cells that migrate to the liver displayed phenotypic and functional changes, suggesting that the liver environment modifies NK cell receptor expression and functional responsiveness. Notably, IL-10 is present at high levels within the liver, and in vivo blockade of IL-10R resulted in a decreased percentage of intrahepatic NKG2A(+)Ly49(-) NK cells. These data suggest that the liver environment regulates NK cell receptor expression and that IL-10 contributes to the regulation of liver NK cells, in part, by maintaining a greater percentage of the hyporesponsive NKG2A(+)Ly49(-) NK cells in the liver.

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References

Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T . Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004; 173(10):6072-81. DOI: 10.4049/jimmunol.173.10.6072. View

Yoshidome H, Kato A, Edwards M, Lentsch A . Interleukin-10 inhibits pulmonary NF-kappaB activation and lung injury induced by hepatic ischemia-reperfusion. Am J Physiol. 1999; 277(5):L919-23. DOI: 10.1152/ajplung.1999.277.5.L919. View

Williams N, Kubota A, Bennett M, Kumar V, Takei F . Clonal analysis of NK cell development from bone marrow progenitors in vitro: orderly acquisition of receptor gene expression. Eur J Immunol. 2000; 30(7):2074-82. DOI: 10.1002/1521-4141(200007)30:7<2074::AID-IMMU2074>3.0.CO;2-#. View

Vosshenrich C, Samson-Villeger S, Di Santo J . Distinguishing features of developing natural killer cells. Curr Opin Immunol. 2005; 17(2):151-8. DOI: 10.1016/j.coi.2005.01.005. View

Crispe I . Hepatic T cells and liver tolerance. Nat Rev Immunol. 2003; 3(1):51-62. DOI: 10.1038/nri981. View

Chaix J, Tessmer M, Hoebe K, Fuseri N, Ryffel B, Dalod M . Cutting edge: Priming of NK cells by IL-18. J Immunol. 2008; 181(3):1627-31. PMC: 5154249. DOI: 10.4049/jimmunol.181.3.1627. View

Tu Z, Bozorgzadeh A, Pierce R, Kurtis J, Crispe I, Orloff M . TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med. 2008; 205(1):233-44. PMC: 2234385. DOI: 10.1084/jem.20072195. View

Della Chiesa M, Vitale M, Carlomagno S, Ferlazzo G, Moretta L, Moretta A . The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors. Eur J Immunol. 2003; 33(6):1657-66. DOI: 10.1002/eji.200323986. View

Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H . Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001; 19:423-74. DOI: 10.1146/annurev.immunol.19.1.423. View

10.

Hayakawa Y, Smyth M . CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol. 2006; 176(3):1517-24. DOI: 10.4049/jimmunol.176.3.1517. View

11.

Pascal V, Nathan N, Claudio E, Siebenlist U, Anderson S . NF-kappa B p50/p65 affects the frequency of Ly49 gene expression by NK cells. J Immunol. 2007; 179(3):1751-9. DOI: 10.4049/jimmunol.179.3.1751. View

12.

Khakoo S, Thio C, Martin M, Brooks C, Gao X, Astemborski J . HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004; 305(5685):872-4. DOI: 10.1126/science.1097670. View

13.

Klugewitz K, Blumenthal-Barby F, Eulenburg K, Emoto M, Hamann A . The spectrum of lymphoid subsets preferentially recruited into the liver reflects that of resident populations. Immunol Lett. 2004; 93(2-3):159-62. DOI: 10.1016/j.imlet.2004.03.007. View

14.

Sivakumar P, Gunturi A, Salcedo M, Schatzle J, Lai W, Kurepa Z . Cutting edge: expression of functional CD94/NKG2A inhibitory receptors on fetal NK1.1+Ly-49- cells: a possible mechanism of tolerance during NK cell development. J Immunol. 1999; 162(12):6976-80. View

15.

Andrews D, Scalzo A, Yokoyama W, Smyth M, Degli-Esposti M . Functional interactions between dendritic cells and NK cells during viral infection. Nat Immunol. 2002; 4(2):175-81. DOI: 10.1038/ni880. View

16.

Maroof A, Beattie L, Zubairi S, Svensson M, Stager S, Kaye P . Posttranscriptional regulation of II10 gene expression allows natural killer cells to express immunoregulatory function. Immunity. 2008; 29(2):295-305. PMC: 2656759. DOI: 10.1016/j.immuni.2008.06.012. View

17.

Guidotti L, Chisari F . Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol. 2007; 1:23-61. DOI: 10.1146/annurev.pathol.1.110304.100230. View

18.

Jinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N . Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology. 2006; 120(1):73-82. PMC: 2265878. DOI: 10.1111/j.1365-2567.2006.02479.x. View

19.

Dorfman J, Raulet D . Acquisition of Ly49 receptor expression by developing natural killer cells. J Exp Med. 1998; 187(4):609-18. PMC: 2212149. DOI: 10.1084/jem.187.4.609. View

20.

Adams D, Eksteen B, Curbishley S . Immunology of the gut and liver: a love/hate relationship. Gut. 2008; 57(6):838-48. DOI: 10.1136/gut.2007.122168. View