Abstract
Invariant chain (Ii) or CD74 is a non-polymorphic glycoprotein, which apart from its role as a chaperone dedicated to MHCII molecules, is known to be a high-affinity receptor for macrophage migration inhibitory factor (MIF). The present study aimed to define the roles of CD74 and MIF in the immune surveillance escape process. Towards this direction, the cell lines HL-60, Raji, K562 and primary pre-B leukemic cells were examined for expression and secretion of MIF. Flow cytometry analysis detected high levels of MIF and intracellular/membrane CD74 expression in all leukemic cells tested, while MIF secretion was shown to be inversely proportional to intracellular HLA-DR (DR) expression. In the MHCII-negative cells, IFN-γ increased MIF expression and induced its secretion in HL-60 and K562 cells, respectively. In K562 cells, CD74 (Iip33Iip35) was shown to co-precipitate with HLA-DOβ (DOβ), inhibiting thus MIF or DR binding. Induced expression of DOα in K562 (DOα-DOβ+) cells in different transfection combinations decreased MIF expression and secretion, while increasing surface DR expression. Thus, MIF could indeed be part of the antigen presentation process.
Acknowledgments
This work was supported by the General Secretariat for Research and Technology (75%) and the European Community State (25%), as well as the national funding of the Ministry of Education and the Special Account for Research Resources of the University of Crete through services to the private sector.
Conflict of interest disclosure: The authors declare no commercial or financial conflict of interest.
References
Athanassakis, I. and Iconomidou, B. (1996). Cytokine production in the serum and spleen of mice from day 6 to 14 of gestation. Dev. Immunol. 4, 247–255.10.1155/1995/42412Search in Google Scholar
Bendrat, K., Al-Abed, Y., Callaway, D.J., Peng, T., Calandra, T., Metz, C.N., and Bucala, R. (1997). Biochemical and mutational investigations of the enzymatic activity of macrophage migration inhibitory factor. Biochemistry 36, 15356–15362.10.1021/bi971153aSearch in Google Scholar
Bernhagen, J., Krohn, R., Lue, H., Gregory, J.L., Zernecke, A., Koenen, R.R., Dewor, M., Georgiev, I., Schober, A., Leng, L., et al. (2007). MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med. 13, 587–596.10.1038/nm1567Search in Google Scholar
Bloom, B.R. and Glade, P.R. (1971). Methods in cell-mediated immunity (New York, USA: Academic Press).10.1056/NEJM197105272842111Search in Google Scholar
Brown, A.M., Wright, K.L., and Ting, J.P. (1993). Human major histocompatibility complex class II-associated invariant chain gene promoter. Functional analysis and in vivo protein/DNA interactions of constitutive and IFN-γ-induced expression. J. Biol. Chem. 268, 26328–26333.10.1016/S0021-9258(19)74318-XSearch in Google Scholar
Busch, R. and Mellins, E.D. (1996). Developing and shedding inhibitors: how MHC class II molecules reach maturity. Current Opin. Immunol. 8, 51–58.10.1016/S0952-7915(96)80105-1Search in Google Scholar
Busch, R., Rinderknecht, C.H., Roh, S., Lee, A.W., Harding, J.J., Buster, T., Hornell, T.M., and Mellins, E.D. (2005). Achieving stability through editing and chaperoning: regulation of MHC II peptide binding and expression. Immunol. Rev. 207, 242–260.10.1111/j.0105-2896.2005.00306.xSearch in Google Scholar PubMed
Calandra, T. and Roger, T. (2003). Macrophage migration inhibitory factor: a regulator of innate immunity. Nat. Rev. Immunol. 3, 791–800.10.1038/nri1200Search in Google Scholar PubMed PubMed Central
Calandra, T., Echtenacher, B., Roy, D.L., Pugin, J., Metz, C.N., Hultner, L., Heumann, D., Mannel, D., Bucala, R., and Glauser, M.P. (2000). Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat. Med. 6, 164–170.10.1038/72262Search in Google Scholar PubMed
Cloutier, M., Gauthier, C., Fortin, J.S., and Thibodeau, J. (2014). The invariant chain p35 isoform promotes formation of nonameric complexes with MHC II molecules. Immunol. Cell Biol. 92, 553–556.10.1038/icb.2014.17Search in Google Scholar PubMed
Conroy, H., Mawhinney, L., and Donnelly, S.C. (2010). Inflammation and cancer: macrophage migration inhibitory factor (MIF) – the potential missing link. Q. J. Med. 103, 831–836.10.1093/qjmed/hcq148Search in Google Scholar
de Jong, Y.P., Abadia-Molina, A.C., Satoskar, A.R., Clarke, K., Rietdijk, S.T., Faubion, W.A., Mizoguchi, E., Metz, C.N., Alsahli, M., ten Hove, T., et al. (2001). Development of chronic colitis is dependent on the cytokine MIF. Nat. Immunol. 2, 1061–1066.10.1038/ni720Search in Google Scholar
Denzin, L.K., Sant’Angelo, D.B., Hammond, C., Surman, M.J., and Cresswell, P. (1997). Negative regulation by HLA-DO of MHC class II-restricted antigen processing. Science 278, 106–109.10.1126/science.278.5335.106Search in Google Scholar
Donnelly, S.C., Haslett, C., Reid, P.T., Grant, I.S., Wallace, W.A., Metz, C.N., Bruce, L.J., and Bucala, R. (1997). Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat. Med. 3, 320–323.10.1038/nm0397-320Search in Google Scholar
Fortin, J.S., Cloutier, M., and Thibodeau, J. (2013). Exposing the specific roles of the invariant chain isoforms in shaping the MHC class II peptidome. Frontiers Immunol. 4, 1–8.10.3389/fimmu.2013.00443Search in Google Scholar
Gregory, J.L., Morand, E.F., McKeown, S.J., Ralph, J.A., Hall, P., Yang, Y.H., McColl, S.R., and Hickey, M.J. (2006). Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2. J. Immunol. 177, 8072–8079.10.4049/jimmunol.177.11.8072Search in Google Scholar
Henne, C., Schwenk, F., Koch, N., and Möller, P. (1995). Surface expression of the invariant chain (CD74) is independent of concomitant expression of major histocompatibility complex class II antigens. Immunol. 84, 177–182.Search in Google Scholar
Kleemann, R., Kapurniotu, A., Frank, R.W., Gessner, A., Mischke, R., Flieger, O., Juttner, S., Brunner, H., and Bernhagen, J. (1998). Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J. Mol. Biol. 280, 85–102.10.1006/jmbi.1998.1864Search in Google Scholar
Koch, H. and Harris, A.W. (1984). Differential expression of the invariant chain in mouse tumor cells: relationship to B lymphoid development. J. Immunol. 132, 12–15.10.4049/jimmunol.132.1.12Search in Google Scholar
Kropshofer, H., Vogt, A.B., Moldenhauer, J., Hammer, J., Blum, J.S., and Hammerling, G.J. (1996). Editing of the HLA-DR-peptide repertoire by HLA-DM. EMBO J. 15, 6144–6154.10.1002/j.1460-2075.1996.tb01002.xSearch in Google Scholar
Leng, L. and Bucala, R. (2006). Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor. Cell Res. 16, 162–168.10.1038/sj.cr.7310022Search in Google Scholar
Lue, H., Kleemann, R., Calandra, T., Roger, T., and Bernhagen, J. (2002). Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microb. Infect. 4, 449–460.10.1016/S1286-4579(02)01560-5Search in Google Scholar
Mischke, R., Kleemann, R., Brunner, H., and Bernhagen, J. (1998). Cross-linking and mutational analysis of the oligomerization state of the cytokine macrophage migration inhibitory factor (MIF). FEBS Lett. 427, 85–90.10.1016/S0014-5793(98)00400-1Search in Google Scholar
Mitchell, R.A., Metz, C.N., Peng, T., and Bucala, R. (1999). Sustained mitogenactivated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J. Biol. Chem. 274, 18100–18106.10.1074/jbc.274.25.18100Search in Google Scholar
Morris, P., Shaman, J., Attaya, M., Amaya, S., Goodman, C., Bergman, J.J., Monaco, J.J., and Mellins, E. (1994). An essential role for HLA-DM in antigen presentation by class II major histocompatibility molecules. Nature 368, 551–554.10.1038/368551a0Search in Google Scholar
Naujokas, M.F., Morin, M., Anderson, M.S., Peterson, M., and Miller, J. (1993). The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44. Cell 74, 257–268.10.1016/0092-8674(93)90417-OSearch in Google Scholar
Onodera, S., Kaneda, K., Mizue, Y., Koyama, Y., Fujinaga, M., and Nishihira, J. (2000). Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. J. Biol. Chem. 275, 444–450.10.1074/jbc.275.1.444Search in Google Scholar PubMed
Papadimitriou, L., Morianos, I., Michailidou, V., Dionyssopoulou, E., Vassiliadis, S., and Athanassakis, I. (2008). Characterization of intracellular HLA-DR, DM and DO profile in K562 and HL-60 leukemic cells. Mol. Immunol. 45, 3965–3973.10.1016/j.molimm.2008.06.017Search in Google Scholar PubMed
Papadimitriou, L., Zerva, I., Georgouli, M., Makatounakis, T., Papamatheakis, J., and Athanassakis, I. (2013). DOα-β+ expression in favor of HLA-DR engagement in exosomes. Immunobiology 218, 1019–1025.10.1016/j.imbio.2012.12.003Search in Google Scholar PubMed
Potolicchio, I., Santambrogio, L., and Strominger, J.L. (2003). Molecular interaction and enzymatic activity of macrophage migration inhibitory factor with immunorelevant peptides. J. Biol. Chem. 278, 30889–30895.10.1074/jbc.M302854200Search in Google Scholar PubMed
Tesch, G.H., Nikolic-Paterson, D.J., Metz, C.N., Mu, W., Bacher, M., Bucala, R., Atkins, R.C., and Lan, H,Y. (1998). Rat mesangial cells express macrophage migration inhibitory factor in vitro and in vivo. J. Am. Soc. Nephrol. 9, 417–424.10.1681/ASN.V93417Search in Google Scholar PubMed
Qiu, Y., Xu, X., Wandinger-Ness, A., Dalke, D.P., and Pierce, S.K. (1994). Separation of subcellular compartments containing distinct functional forms of MHC class II. J. Cell Biol. 125, 595–605.10.1083/jcb.125.3.595Search in Google Scholar PubMed PubMed Central
Ranella, A., Vassiliadis, S., Mastora, C., Michailidou, V., Dionyssopoulou, E., and Athanassakis, I. (2005). Constitutive intracellular expression of HLA-DO and HLA-DR but not HLA-DM in trophoblast cells. Hum. Immunol. 66, 43–55.10.1016/j.humimm.2004.10.002Search in Google Scholar
Rosengren, E., Bucala, R., Aman, P., Jacobsson, L., Odh, G., Metz, C.N., and Rorsman, H. (1996). The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol. Med. 2, 143–149.10.1007/BF03402210Search in Google Scholar
Sand, K.M., Landsverk, O.J., Berg-Larsen, A., Bakke, O., and Gregers, T.F. (2014). The human-specific invariant chain isoform Iip35 modulates Iip33 trafficking and function. Immunol. Cell Biol. 92, 791–798.10.1038/icb.2014.54Search in Google Scholar
Santos, L.L. and Morand, E.F. (2009). Macrophage migration inhibitory factor: a key cytokine in RA, SLE and atherosclerosis. Clin. Chim. Acta 399, 1–7.10.1016/j.cca.2008.09.014Search in Google Scholar
Tonnelle, C., DeMars, R., and Long, E.O. (1985). DOβ: a new β chain gene in HLA-D with distinct regulation of expression. EMBO J. 4, 2839–2847.10.1002/j.1460-2075.1985.tb04012.xSearch in Google Scholar
vam Ham, S.M., van Lith, M., Lillemeir, B.F., Tjin, E., Gruneberg, U., Rahman, D., Pastoors, L., van Meijgaarden, K., Roucard, C., Trowsdale, J., et al. (2000). Modulation of the major histocompatibility complex class II associated repertoire by human histocompatibility leukocyte antigen (HLA)-DO. J. Exp. Med. 191, 1127–1136.10.1084/jem.191.7.1127Search in Google Scholar
Wake, C.T. and Flavell, R.A. (1985). Multiple mechanisms regulate the expression of murine immune response genes. Cell 42, 623–628.10.1016/0092-8674(85)90119-9Search in Google Scholar
Warmerdam, P.A., Long, E.O., and Roche, P.A. (1996). Isoforms of the invariant chain regulate transport of MHC class II molecules to antigen processing compartments. J. Cell Biol. 133, 281–291.10.1083/jcb.133.2.281Search in Google Scholar PubMed PubMed Central
Weiser, W.Y., Temple, P.A., Witek-Giannotti, J.S., Remold, H.G., Clark, S.C., and David, J.R. (1989). Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc. Natl. Acad. Sci. USA 86, 7522–7526.10.1073/pnas.86.19.7522Search in Google Scholar PubMed PubMed Central
Xiu, F., Côté, M.H., Bourgeois-Daigneault, M.C., Brunet, A., Gauvreau, M.É., Shaw, A., and Thibodeau, J. (2011). Cutting edge: HLA-DO impairs the incorporation of HLA-DM into exosomes. J. Immunol. 187, 1547–1551.10.4049/jimmunol.1100199Search in Google Scholar PubMed
Zwart, W., Peperzak, V., de Vries, E., Keller, A.M., van der Horst, G., Veraar, E.A., Geumann, U., Janssen, H., Janssen, L., Naik, S.H., et al. (2010). The invariant chain transports TNF family member CD70 to MHC class II compartments in dendritic cells. J. Cell Sci. 123, 3817–3827.10.1242/jcs.068510Search in Google Scholar PubMed
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