T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease
Abstract
:1. Introduction
2. T Cells as Part of the Innate and Adaptive Hepatic Immune System
Classification of T Cells
3. Roles of Different T Cell Subsets in Nonalcoholic Fatty Liver Disease (NAFLD)
3.1. γδ T Cells
3.2. Cluster of Differentiation (CD)4+ T Cells
3.2.1. CD4+ T Helper Cells
3.2.2. CD4+ Regulatory T Cells
3.3. CD8+ Cytotoxic T Cells
3.4. Natural Killer (NK)T Cells
3.5. Mucosal-Associated Invariant T (MAIT) Cells
4. T Cells and the Gut-Liver Axis
5. NK Cells
5.1. Functional Competencies of NK Cells in NAFLD
5.2. NK Cells and Gut-Liver Axis
6. Concluding Remarks and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
- Filip, R.; Radzki, R.P.; Bienko, M. Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis. Clin. Interv. Aging 2018, 13, 1879–1891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gastaldelli, A.; Cusi, K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep. 2019, 1, 312–328. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mirrakhimov, A.E.; Polotsky, V.Y. Obstructive sleep apnea and non-alcoholic Fatty liver disease: Is the liver another target? Front. Neurol. 2012, 3, 149. [Google Scholar] [CrossRef] [Green Version]
- Vassilatou, E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J. Gastroenterol. 2014, 20, 8351–8363. [Google Scholar] [CrossRef]
- Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heymann, F.; Tacke, F. Immunology in the liver--from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 88–110. [Google Scholar] [CrossRef] [PubMed]
- Jenne, C.N.; Kubes, P. Immune surveillance by the liver. Nat. Immunol. 2013, 14, 996–1006. [Google Scholar] [CrossRef]
- Meli, R.; Mattace Raso, G.; Calignano, A. Role of innate immune response in non-alcoholic Fatty liver disease: Metabolic complications and therapeutic tools. Front. Immunol. 2014, 5, 177. [Google Scholar] [CrossRef] [Green Version]
- Lanthier, N.; Molendi-Coste, O.; Cani, P.D.; van Rooijen, N.; Horsmans, Y.; Leclercq, I.A. Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet. FASEB J. 2011, 25, 4301–4311. [Google Scholar] [CrossRef]
- Syn, W.K.; Oo, Y.H.; Pereira, T.A.; Karaca, G.F.; Jung, Y.; Omenetti, A.; Witek, R.P.; Choi, S.S.; Guy, C.D.; Fearing, C.M.; et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 2010, 51, 1998–2007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martinez-Chantar, M.L.; Delgado, T.C.; Beraza, N. Revisiting the Role of Natural Killer Cells in Non-Alcoholic Fatty Liver Disease. Front. Immunol. 2021, 12, 322. [Google Scholar] [CrossRef]
- Van Herck, M.A.; Weyler, J.; Kwanten, W.J.; Dirinck, E.L.; De Winter, B.Y.; Francque, S.M.; Vonghia, L. The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity. Front. Immunol. 2019, 10, 82. [Google Scholar] [CrossRef] [Green Version]
- Bluher, M. Adipose tissue inflammation: A cause or consequence of obesity-related insulin resistance? Clin. Sci. 2016, 130, 1603–1614. [Google Scholar] [CrossRef]
- Vonghia, L.; Michielsen, P.; Francque, S. Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int. J. Mol. Sci. 2013, 14, 19867–19890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Narayanan, S.; Surette, F.A.; Hahn, Y.S. The Immune Landscape in Nonalcoholic Steatohepatitis. Immune. Netw. 2016, 16, 147–158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davies, L.C.; Jenkins, S.J.; Allen, J.E.; Taylor, P.R. Tissue-resident macrophages. Nat. Immunol. 2013, 14, 986–995. [Google Scholar] [CrossRef] [PubMed]
- Viret, C.; Janeway, C.A., Jr. MHC and T cell development. Rev. Immunogenet. 1999, 1, 91–104. [Google Scholar] [PubMed]
- Rossjohn, J.; Gras, S.; Miles, J.J.; Turner, S.J.; Godfrey, D.I.; McCluskey, J. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 2015, 33, 169–200. [Google Scholar] [CrossRef] [PubMed]
- Scaviner, D.; Lefranc, M.P. The human T cell receptor alpha variable (TRAV) genes. Exp. Clin. Immunogenet. 2000, 17, 83–96. [Google Scholar] [CrossRef] [Green Version]
- Bhati, M.; Cole, D.K.; McCluskey, J.; Sewell, A.K.; Rossjohn, J. The versatility of the alphabeta T-cell antigen receptor. Protein. Sci. 2014, 23, 260–272. [Google Scholar] [CrossRef] [Green Version]
- Vantourout, P.; Hayday, A. Six-of-the-best: Unique contributions of gammadelta T cells to immunology. Nat. Rev. Immunol. 2013, 13, 88–100. [Google Scholar] [CrossRef] [Green Version]
- Li, Q.J.; Dinner, A.R.; Qi, S.; Irvine, D.J.; Huppa, J.B.; Davis, M.M.; Chakraborty, A.K. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat. Immunol. 2004, 5, 791–799. [Google Scholar] [CrossRef]
- Holler, P.D.; Kranz, D.M. Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity 2003, 18, 255–264. [Google Scholar] [CrossRef] [Green Version]
- Treiner, E.; Duban, L.; Bahram, S.; Radosavljevic, M.; Wanner, V.; Tilloy, F.; Affaticati, P.; Gilfillan, S.; Lantz, O. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 2003, 422, 164–169. [Google Scholar] [CrossRef] [PubMed]
- Fabbri, M.; Smart, C.; Pardi, R. T lymphocytes. Int. J. Biochem. Cell Biol. 2003, 35, 1004–1008. [Google Scholar] [CrossRef]
- Hayday, A.C. γδ cells: A right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 2000, 18, 975–1026. [Google Scholar] [CrossRef]
- Kenna, T.; Golden-Mason, L.; Norris, S.; Hegarty, J.E.; O’Farrelly, C.; Doherty, D.G. Distinct subpopulations of gamma delta T cells are present in normal and tumor-bearing human liver. Clin. Immunol. 2004, 113, 56–63. [Google Scholar] [CrossRef]
- Gao, B.; Jeong, W.I.; Tian, Z. Liver: An organ with predominant innate immunity. Hepatology 2008, 47, 729–736. [Google Scholar] [CrossRef]
- Torres-Hernandez, A.; Wang, W.; Nikiforov, Y.; Tejada, K.; Torres, L.; Kalabin, A.; Adam, S.; Wu, J.; Lu, L.; Chen, R.; et al. gammadelta T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming. Hepatology 2020, 71, 477–494. [Google Scholar] [CrossRef] [PubMed]
- Castano-Rodriguez, N.; Mitchell, H.M.; Kaakoush, N.O. NAFLD, Helicobacter species and the intestinal microbiome. Best Pract. Res. Clin. Gastroenterol. 2017, 31, 657–668. [Google Scholar] [CrossRef] [PubMed]
- Ribeiro, S.T.; Ribot, J.C.; Silva-Santos, B. Five Layers of Receptor Signaling in gammadelta T-Cell Differentiation and Activation. Front. Immunol. 2015, 6, 15. [Google Scholar] [CrossRef] [Green Version]
- Lombes, A.; Durand, A.; Charvet, C.; Riviere, M.; Bonilla, N.; Auffray, C.; Lucas, B.; Martin, B. Adaptive Immune-like gamma/delta T Lymphocytes Share Many Common Features with Their alpha/beta T Cell Counterparts. J. Immunol. 2015, 195, 1449–1458. [Google Scholar] [CrossRef] [Green Version]
- Her, Z.; Tan, J.H.L.; Lim, Y.S.; Tan, S.Y.; Chan, X.Y.; Tan, W.W.S.; Liu, M.; Yong, K.S.M.; Lai, F.; Ceccarello, E.; et al. CD4(+) T Cells Mediate the Development of Liver Fibrosis in High Fat Diet-Induced NAFLD in Humanized Mice. Front. Immunol. 2020, 11, 580968. [Google Scholar] [CrossRef]
- Li, F.; Hao, X.; Chen, Y.; Bai, L.; Gao, X.; Lian, Z.; Wei, H.; Sun, R.; Tian, Z. The microbiota maintain homeostasis of liver-resident gammadeltaT-17 cells in a lipid antigen/CD1d-dependent manner. Nat. Commun. 2017, 7, 13839. [Google Scholar] [CrossRef]
- Dutton, R.W.; Bradley, L.M.; Swain, S.L. T cell memory. Annu. Rev. Immunol. 1998, 16, 201–223. [Google Scholar] [CrossRef]
- Raphael, I.; Nalawade, S.; Eagar, T.N.; Forsthuber, T.G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015, 74, 5–17. [Google Scholar] [CrossRef] [Green Version]
- Shinkai, K.; Mohrs, M.; Locksley, R.M. Helper T cells regulate type-2 innate immunity in vivo. Nature 2002, 420, 825–829. [Google Scholar] [CrossRef] [PubMed]
- Ma, C.; Kesarwala, A.H.; Eggert, T.; Medina-Echeverz, J.; Kleiner, D.E.; Jin, P.; Stroncek, D.F.; Terabe, M.; Kapoor, V.; ElGindi, M.; et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016, 531, 253–257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schmidt, A.M.; Lu, W.; Sindhava, V.J.; Huang, Y.; Burkhardt, J.K.; Yang, E.; Riese, M.J.; Maltzman, J.S.; Jordan, M.S.; Kambayashi, T. Regulatory T cells require TCR signaling for their suppressive function. J. Immunol. 2015, 194, 4362–4370. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barbi, J.; Pardoll, D.; Pan, F. Metabolic control of the Treg/Th17 axis. Immunol. Rev. 2013, 252, 52–77. [Google Scholar] [CrossRef] [Green Version]
- Dowling, M.R.; Kan, A.; Heinzel, S.; Marchingo, J.M.; Hodgkin, P.D.; Hawkins, E.D. Regulatory T Cells Suppress Effector T Cell Proliferation by Limiting Division Destiny. Front. Immunol. 2018, 9, 2461. [Google Scholar] [CrossRef] [PubMed]
- Mehrfeld, C.; Zenner, S.; Kornek, M.; Lukacs-Kornek, V. The Contribution of Non-Professional Antigen-Presenting Cells to Immunity and Tolerance in the Liver. Front. Immunol. 2018, 9, 635. [Google Scholar] [CrossRef] [PubMed]
- Lalazar, G.; Mizrahi, M.; Turgeman, I.; Adar, T.; Ben Ya’acov, A.; Shabat, Y.; Nimer, A.; Hemed, N.; Zolotarovya, L.; Lichtenstein, Y.; et al. Oral Administration of OKT3 MAb to Patients with NASH, Promotes Regulatory T-cell Induction, and Alleviates Insulin Resistance: Results of a Phase IIa Blinded Placebo-Controlled Trial. J. Clin. Immunol. 2015, 35, 399–407. [Google Scholar] [CrossRef]
- Dywicki, J.; Buitrago-Molina, L.E.; Noyan, F.; Davalos-Misslitz, A.C.; Hupa-Breier, K.L.; Lieber, M.; Hapke, M.; Schlue, J.; Falk, C.S.; Raha, S.; et al. The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis. Hepatol. Commun. 2021. [Google Scholar] [CrossRef]
- Liu, X.; Zhang, P.; Martin, R.C.; Cui, G.; Wang, G.; Tan, Y.; Cai, L.; Lv, G.; Li, Y. Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice. Am. J. Cancer Res. 2016, 6, 1011–1025. [Google Scholar] [PubMed]
- Bonora, E.; Targher, G. Increased risk of cardiovascular disease and chronic kidney disease in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 372–381. [Google Scholar] [CrossRef] [PubMed]
- Bhattacharjee, J.; Kirby, M.; Softic, S.; Miles, L.; Salazar-Gonzalez, R.M.; Shivakumar, P.; Kohli, R. Hepatic Natural Killer T-cell and CD8+ T-cell Signatures in Mice with Nonalcoholic Steatohepatitis. Hepatol. Commun. 2017, 1, 299–310. [Google Scholar] [CrossRef] [Green Version]
- Breuer, D.A.; Pacheco, M.C.; Washington, M.K.; Montgomery, S.A.; Hasty, A.H.; Kennedy, A.J. CD8(+) T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 318, G211–G224. [Google Scholar] [CrossRef]
- Koda, Y.; Teratani, T.; Chu, P.S.; Hagihara, Y.; Mikami, Y.; Harada, Y.; Tsujikawa, H.; Miyamoto, K.; Suzuki, T.; Taniki, N.; et al. CD8(+) tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat. Commun. 2021, 12, 4474. [Google Scholar] [CrossRef]
- Wang, T.; Sun, G.; Wang, Y.; Li, S.; Zhao, X.; Zhang, C.; Jin, H.; Tian, D.; Liu, K.; Shi, W.; et al. The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis. FASEB J. 2019, 33, 8490–8503. [Google Scholar] [CrossRef] [PubMed]
- Winau, F.; Hegasy, G.; Weiskirchen, R.; Weber, S.; Cassan, C.; Sieling, P.A.; Modlin, R.L.; Liblau, R.S.; Gressner, A.M.; Kaufmann, S.H. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 2007, 26, 117–129. [Google Scholar] [CrossRef] [Green Version]
- Maricic, I.; Sheng, H.; Marrero, I.; Seki, E.; Kisseleva, T.; Chaturvedi, S.; Molle, N.; Mathews, S.A.; Gao, B.; Kumar, V. Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology 2015, 61, 1357–1369. [Google Scholar] [CrossRef] [Green Version]
- Li, Y.; Huang, B.; Jiang, X.; Chen, W.; Zhang, J.; Wei, Y.; Chen, Y.; Lian, M.; Bian, Z.; Miao, Q.; et al. Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization. Front. Immunol. 2018, 9, 1994. [Google Scholar] [CrossRef]
- Hegde, P.; Weiss, E.; Paradis, V.; Wan, J.; Mabire, M.; Sukriti, S.; Rautou, P.E.; Albuquerque, M.; Picq, O.; Gupta, A.C.; et al. Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver. Nat. Commun. 2018, 9, 2146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chassaing, B.; Etienne-Mesmin, L.; Gewirtz, A.T. Microbiota-liver axis in hepatic disease. Hepatology 2014, 59, 328–339. [Google Scholar] [CrossRef] [Green Version]
- Luoma, A.M.; Castro, C.D.; Adams, E.J. gammadelta T cell surveillance via CD1 molecules. Trends Immunol. 2014, 35, 613–621. [Google Scholar] [CrossRef]
- Liang, Q.; Zhang, M.; Hu, Y.; Zhang, W.; Zhu, P.; Chen, Y.; Xue, P.; Li, Q.; Wang, K. Gut Microbiome Contributes to Liver Fibrosis Impact on T Cell Receptor Immune Repertoire. Front. Microbiol. 2020, 11, 571847. [Google Scholar] [CrossRef] [PubMed]
- Gebru, Y.A.; Choi, M.R.; Raja, G.; Gupta, H.; Sharma, S.P.; Choi, Y.R.; Kim, H.S.; Yoon, S.J.; Kim, D.J.; Suk, K.T. Pathophysiological Roles of Mucosal-Associated Invariant T Cells in the Context of Gut Microbiota-Liver Axis. Microorganisms 2021, 9, 296. [Google Scholar] [CrossRef]
- Marrero, I.; Maricic, I.; Feldstein, A.E.; Loomba, R.; Schnabl, B.; Rivera-Nieves, J.; Eckmann, L.; Kumar, V. Complex Network of NKT Cell Subsets Controls Immune Homeostasis in Liver and Gut. Front. Immunol. 2018, 9, 2082. [Google Scholar] [CrossRef] [PubMed]
- Spits, H.; Artis, D.; Colonna, M.; Diefenbach, A.; Di Santo, J.P.; Eberl, G.; Koyasu, S.; Locksley, R.M.; McKenzie, A.N.J.; Mebius, R.E.; et al. Innate lymphoid cells—A proposal for uniform nomenclature. Nat. Rev. Immunol. 2013, 13, 145–149. [Google Scholar] [CrossRef]
- Harmon, C.; Robinson, M.W.; Fahey, R.; Whelan, S.; Houlihan, D.D.; Geoghegan, J.; O’Farrelly, C. Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur. J. Immunol. 2016, 46, 2111–2120. [Google Scholar] [CrossRef] [Green Version]
- Moretta, L.; Montaldo, E.; Vacca, P.; Del Zotto, G.; Moretta, F.; Merli, P.; Locatelli, F.; Mingari, M.C. Human natural killer cells: Origin, receptors, function, and clinical applications. Int. Arch. Allergy Immunol. 2014, 164, 253–264. [Google Scholar] [CrossRef] [PubMed]
- Norris, S.; Collins, C.; Doherty, D.G.; Smith, F.; McEntee, G.; Traynor, O.; Nolan, N.; Hegarty, J.; O’Farrelly, C. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J. Hepatol. 1998, 28, 84–90. [Google Scholar] [CrossRef]
- Sarhan, D.; Miller, J.S. Natural Killer Cells: What Have We Learned? In Cell and Gene Therapies; Perales, M.-A., Abutalib, S.A., Bollard, C., Eds.; Springer International Publishing: Cham, Switzerland, 2019; pp. 181–200. [Google Scholar]
- Cooper, M.A.; Fehniger, T.A.; Caligiuri, M.A. The biology of human natural killer-cell subsets. Trends Immunol. 2001, 22, 633–640. [Google Scholar] [CrossRef]
- Stabile, H.; Fionda, C.; Gismondi, A.; Santoni, A. Role of Distinct Natural Killer Cell Subsets in Anticancer Response. Front. Immunol. 2017, 8, 293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sivori, S.; Vitale, M.; Bottino, C.; Marcenaro, E.; Sanseverino, L.; Parolini, S.; Moretta, L.; Moretta, A. CD94 functions as a natural killer cell inhibitory receptor for different HLA class I alleles: Identification of the inhibitory form of CD94 by the use of novel monoclonal antibodies. Eur. J. Immunol. 1996, 26, 2487–2492. [Google Scholar] [CrossRef]
- Moretta, L.; Moretta, A. Unravelling natural killer cell function: Triggering and inhibitory human NK receptors. EMBO J. 2004, 23, 255–259. [Google Scholar] [CrossRef] [Green Version]
- Kärre, K. Natural killer cell recognition of missing self. Nat. Immunol. 2008, 9, 477–480. [Google Scholar] [CrossRef]
- Di Vito, C.; Mikulak, J.; Mavilio, D. On the Way to Become a Natural Killer Cell. Front. Immunol. 2019, 10, 1812. [Google Scholar] [CrossRef]
- Trapani, J.A.; Smyth, M.J. Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol. 2002, 2, 735–747. [Google Scholar] [CrossRef]
- Romee, R.; Foley, B.; Lenvik, T.; Wang, Y.; Zhang, B.; Ankarlo, D.; Luo, X.; Cooley, S.; Verneris, M.; Walcheck, B.; et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013, 121, 3599–3608. [Google Scholar] [CrossRef]
- Vossen, M.T.M.; Matmati, M.; Hertoghs, K.M.L.; Baars, P.A.; Gent, M.-R.; Leclercq, G.; Hamann, J.; Kuijpers, T.W.; van Lier, R.A.W. CD27 Defines Phenotypically and Functionally Different Human NK Cell Subsets. J. Immunol. 2008, 180, 3739. [Google Scholar] [CrossRef] [Green Version]
- Gao, B.; Radaeva, S.; Jeong, W.I. Activation of natural killer cells inhibits liver fibrosis: A novel strategy to treat liver fibrosis. Expert. Rev. Gastroenterol. Hepatol. 2007, 1, 173–180. [Google Scholar] [CrossRef]
- Peng, H.; Jiang, X.; Chen, Y.; Sojka, D.K.; Wei, H.; Gao, X.; Sun, R.; Yokoyama, W.M.; Tian, Z. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Investig. 2013, 123, 1444–1456. [Google Scholar] [CrossRef] [Green Version]
- Zhou, J.; Peng, H.; Li, K.; Qu, K.; Wang, B.; Wu, Y.; Ye, L.; Dong, Z.; Wei, H.; Sun, R.; et al. Liver-Resident NK Cells Control Antiviral Activity of Hepatic T Cells via the PD-1-PD-L1 Axis. Immunity 2019, 50, 403–417.e404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sojka, D.K.; Plougastel-Douglas, B.; Yang, L.; Pak-Wittel, M.A.; Artyomov, M.N.; Ivanova, Y.; Zhong, C.; Chase, J.M.; Rothman, P.B.; Yu, J.; et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 2014, 3, e01659. [Google Scholar] [CrossRef]
- Vermijlen, D.; Luo, D.; Froelich, C.J.; Medema, J.P.; Kummer, J.A.; Willems, E.; Braet, F.; Wisse, E. Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway. J. Leukoc. Biol. 2002, 72, 668–676. [Google Scholar] [PubMed]
- Jin, H.; Jia, Y.; Yao, Z.; Huang, J.; Hao, M.; Yao, S.; Lian, N.; Zhang, F.; Zhang, C.; Chen, X.; et al. Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell. Cell. Signal. 2017, 33, 79–85. [Google Scholar] [CrossRef]
- Peng, H.; Sun, R. Liver-resident NK cells and their potential functions. Cell. Mol. Immunol. 2017, 14, 890–894. [Google Scholar] [CrossRef] [PubMed]
- Radaeva, S.; Sun, R.; Jaruga, B.; Nguyen, V.T.; Tian, Z.; Gao, B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006, 130, 435–452. [Google Scholar] [CrossRef]
- Gur, C.; Doron, S.; Kfir-Erenfeld, S.; Horwitz, E.; Abu-Tair, L.; Safadi, R.; Mandelboim, O. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 2012, 61, 885–893. [Google Scholar] [CrossRef]
- Li, T.; Yang, Y.; Song, H.; Li, H.; Cui, A.; Liu, Y.; Su, L.; Crispe, I.N.; Tu, Z. Activated NK cells kill hepatic stellate cells via p38/PI3K signaling in a TRAIL-involved degranulation manner. J. Leukoc. Biol. 2019, 105, 695–704. [Google Scholar] [CrossRef] [PubMed]
- Tian, Z.; Chen, Y.; Gao, B. Natural killer cells in liver disease. Hepatology 2013, 57, 1654–1662. [Google Scholar] [CrossRef]
- Kahraman, A.; Schlattjan, M.; Kocabayoglu, P.; Yildiz-Meziletoglu, S.; Schlensak, M.; Fingas, C.D.; Wedemeyer, I.; Marquitan, G.; Gieseler, R.K.; Baba, H.A.; et al. Major histocompatibility complex class I-related chains A and B (MIC A/B): A novel role in nonalcoholic steatohepatitis. Hepatology 2010, 51, 92–102. [Google Scholar] [CrossRef]
- Michelet, X.; Dyck, L.; Hogan, A.; Loftus, R.M.; Duquette, D.; Wei, K.; Beyaz, S.; Tavakkoli, A.; Foley, C.; Donnelly, R.; et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 2018, 19, 1330–1340. [Google Scholar] [CrossRef]
- Cuff, A.O.; Sillito, F.; Dertschnig, S.; Hall, A.; Luong, T.V.; Chakraverty, R.; Male, V. The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype. Front. Immunol. 2019, 10, 2180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Viel, S.; Besson, L.; Charrier, E.; Marcais, A.; Disse, E.; Bienvenu, J.; Walzer, T.; Dumontet, C. Alteration of Natural Killer cell phenotype and function in obese individuals. Clin. Immunol. 2017, 177, 12–17. [Google Scholar] [CrossRef]
- Tosello-Trampont, A.C.; Krueger, P.; Narayanan, S.; Landes, S.G.; Leitinger, N.; Hahn, Y.S. NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 2016, 63, 799–812. [Google Scholar] [CrossRef] [Green Version]
- Diedrich, T.; Kummer, S.; Galante, A.; Drolz, A.; Schlicker, V.; Lohse, A.W.; Kluwe, J.; Eberhard, J.M.; Schulze Zur Wiesch, J. Characterization of the immune cell landscape of patients with NAFLD. PLoS ONE 2020, 15, e0230307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stiglund, N.; Strand, K.; Cornillet, M.; Stal, P.; Thorell, A.; Zimmer, C.L.; Naslund, E.; Karlgren, S.; Nilsson, H.; Mellgren, G.; et al. Retained NK Cell Phenotype and Functionality in Non-alcoholic Fatty Liver Disease. Front. Immunol. 2019, 10, 1255. [Google Scholar] [CrossRef]
- Boulenouar, S.; Michelet, X.; Duquette, D.; Alvarez, D.; Hogan, A.E.; Dold, C.; O’Connor, D.; Stutte, S.; Tavakkoli, A.; Winters, D.; et al. Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity. Immunity 2017, 46, 273–286. [Google Scholar] [CrossRef] [Green Version]
- Lee, B.C.; Kim, M.S.; Pae, M.; Yamamoto, Y.; Eberle, D.; Shimada, T.; Kamei, N.; Park, H.S.; Sasorith, S.; Woo, J.R.; et al. Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity. Cell Metab. 2016, 23, 685–698. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Amer, J.; Salhab, A.; Noureddin, M.; Doron, S.; Abu-Tair, L.; Ghantous, R.; Mahamid, M.; Safadi, R. Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease. Hepatol. Commun. 2018, 2, 285–298. [Google Scholar] [CrossRef] [PubMed]
- Sanos, S.L.; Diefenbach, A. Isolation of NK cells and NK-like cells from the intestinal lamina propria. Methods Mol. Biol. 2010, 612, 505–517. [Google Scholar] [CrossRef]
- Wu, X.; Tian, Z. Gut-liver axis: Gut microbiota in shaping hepatic innate immunity. Sci. China Life Sci. 2017, 60, 1191–1196. [Google Scholar] [CrossRef]
- Froelich, C.J.; Bankhurst, A.D. Natural killing and antibody-dependent cellular cytotoxicity: Characterization of effector cells by E-rosetting and monoclonal antibodies. Cell. Immunol. 1983, 78, 33–42. [Google Scholar] [CrossRef]
- Herberman, R.B.; Nunn, M.E.; Lavrin, D.H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int. J. Cancer 1975, 16, 216–229. [Google Scholar] [CrossRef]
- Ganal, S.C.; Sanos, S.L.; Kallfass, C.; Oberle, K.; Johner, C.; Kirschning, C.; Lienenklaus, S.; Weiss, S.; Staeheli, P.; Aichele, P.; et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 2012, 37, 171–186. [Google Scholar] [CrossRef] [Green Version]
- Yang, X.; Lu, D.; Zhuo, J.; Lin, Z.; Yang, M.; Xu, X. The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases. Int. J. Biol. Sci. 2020, 16, 2357–2366. [Google Scholar] [CrossRef]
- Dorrestein, P.C.; Mazmanian, S.K.; Knight, R. Finding the missing links among metabolites, microbes, and the host. Immunity 2014, 40, 824–832. [Google Scholar] [CrossRef] [Green Version]
- Nicholson, J.K.; Holmes, E.; Kinross, J.; Burcelin, R.; Gibson, G.; Jia, W.; Pettersson, S. Host-gut microbiota metabolic interactions. Science 2012, 336, 1262–1267. [Google Scholar] [CrossRef] [Green Version]
- Roager, H.M.; Licht, T.R. Microbial tryptophan catabolites in health and disease. Nat. Commun. 2018, 9, 3294. [Google Scholar] [CrossRef] [Green Version]
- Blacher, E.; Levy, M.; Tatirovsky, E.; Elinav, E. Microbiome-Modulated Metabolites at the Interface of Host Immunity. J. Immunol. 2017, 198, 572–580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Korecka, A.; Dona, A.; Lahiri, S.; Tett, A.J.; Al-Asmakh, M.; Braniste, V.; D’Arienzo, R.; Abbaspour, A.; Reichardt, N.; Fujii-Kuriyama, Y.; et al. Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism. NPJ Biofilms Microbiomes 2016, 2, 16014. [Google Scholar] [CrossRef] [Green Version]
- Muku, G.E.; Murray, I.A.; Perdew, G.H. Activation of the Ah Receptor Modulates Gastrointestinal Homeostasis and the Intestinal Microbiome. Curr. Pharmacol. Rep. 2019, 5, 319–331. [Google Scholar] [CrossRef]
- Krishnan, S.; Ding, Y.; Saedi, N.; Choi, M.; Sridharan, G.V.; Sherr, D.H.; Yarmush, M.L.; Alaniz, R.C.; Jayaraman, A.; Lee, K. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Rep. 2018, 23, 1099–1111. [Google Scholar] [CrossRef] [PubMed]
- Shi, Z.; Lei, H.; Chen, G.; Yuan, P.; Cao, Z.; Ser, H.-L.; Zhu, X.; Wu, F.; Liu, C.; Dong, M.; et al. Impaired Intestinal Akkermansia muciniphila and Aryl Hydrocarbon Receptor Ligands Contribute to Nonalcoholic Fatty Liver Disease in Mice. mSystems 2021, 6, e00985-20. [Google Scholar] [CrossRef] [PubMed]
- Esser, C.; Rannug, A. The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology. Pharmacol. Rev. 2015, 67, 259–279. [Google Scholar] [CrossRef] [Green Version]
- Qiu, J.; Heller, J.J.; Guo, X.; Chen, Z.-M.E.; Fish, K.; Fu, Y.-X.; Zhou, L. The Aryl Hydrocarbon Receptor Regulates Gut Immunity through Modulation of Innate Lymphoid Cells. Immunity 2012, 36, 92–104. [Google Scholar] [CrossRef] [Green Version]
- Gutiérrez-Vázquez, C.; Quintana, F.J. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity 2018, 48, 19–33. [Google Scholar] [CrossRef] [Green Version]
- Murray, I.A.; Patterson, A.D.; Perdew, G.H. Aryl hydrocarbon receptor ligands in cancer: Friend and foe. Nat. Rev. Cancer 2014, 14, 801–814. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.H.; Shin, J.H.; Haggadone, M.D.; Sunwoo, J.B. The aryl hydrocarbon receptor is required for the maintenance of liver-resident natural killer cells. J. Exp. Med. 2016, 213, 2249–2257. [Google Scholar] [CrossRef] [PubMed]
T cells | Subsets | TCR | Antigenpresentation | Main Antigen Molecules |
---|---|---|---|---|
Conventional | CD4 T cells | αβTCR | MHC-II | Peptides (Bacterial & host) |
CD8 T cells | αβTCR | MHC-I | Peptides (Bacterial & host) | |
Non-conventional | γδ T cells | γδTCR | MHC not necessary | (Bacterial & host) |
NKT cells | αβTCR | MHC-I like | Lipids & peptides (Bacterial & host) | |
MAIT cells | αβTCR | MHC-I like | Vit-B2 metabolites (Bacterial) |
Studies | Major Findings | Activation/Cytotoxicity | References |
---|---|---|---|
Murine NASH | Increased CD49b+ NKp46+NK cells. They play a role in polarizing Mϕ toward M1-like phenotypes. | Immunoregulatory depends on IFN-γ, but not granzyme | [89] |
Human NAFLD | Decreased frequency of CD56 (dim)NK cells and MAIT cells in PBMC | Less NKG2D | [90] |
Human and murine NAFLD | Adipose tissue NK cells (or ILC1-like cells) contribute to insulin resistance in mice express CD49a. However, no link between the presence and levels of adipose tissue CD49a+ NK cells and the presence of insulin resistance was noted in the investigated patients. | Adipose CD49a+ mixed ILC1s expressed the most IFN-γ, the least granzyme B, and no TRAIL, unlike ILC1s in liver. | [91,92,93] |
Human NAFLD | NAFLD with F3-F4 fibrosis scores exhibited elevated levels of circulating cytotoxic CD56(dim)CD16(+) cells | Inhibition of NK activity correlated with decreased expression of insulin receptors. mTOR/ERK inhibition correlates with decreased CD56 dim insulin receptor expression and NK impairment. | [94] |
Human NAFLD | NK cells were shown to have an important role in regulating liver fibrosis by directly killing activated hepatic stellate cells via the receptors NKG2D, NKp30 and TRAIL the p38/PI3K/AKT pathway | NK cells are activated by both cytokines, such as IL-12 and IL-18, and innate immune stimuli, such as ligation of TLRs. The secretion of IL-18 depends upon activation of the inflammasome, whereas TLRs are stimulated by microbial products. | [83] |
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Gebru, Y.A.; Gupta, H.; Kim, H.S.; Eom, J.A.; Kwon, G.H.; Park, E.; Jeong, J.-J.; Won, S.-M.; Sharma, S.P.; Ganesan, R.; et al. T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2021, 22, 12190. https://doi.org/10.3390/ijms222212190
Gebru YA, Gupta H, Kim HS, Eom JA, Kwon GH, Park E, Jeong J-J, Won S-M, Sharma SP, Ganesan R, et al. T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences. 2021; 22(22):12190. https://doi.org/10.3390/ijms222212190
Chicago/Turabian StyleGebru, Yoseph Asmelash, Haripriya Gupta, Hyeong Seop Kim, Jung A. Eom, Goo Hyun Kwon, Eunju Park, Jin-Ju Jeong, Sung-Min Won, Satya Priya Sharma, Raja Ganesan, and et al. 2021. "T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease" International Journal of Molecular Sciences 22, no. 22: 12190. https://doi.org/10.3390/ijms222212190