Abstract
Purpose. The aim of this study was to use small unilamellar liposomeswith incorporated MHC II/peptide complexes as a carrier system formultivalent antigen presentation to CD4 + T cells.
Methods. Purified peptide pre-loaded MHC II molecules wereincorporated into small unilamellar liposomes and tested for their ability toactivate A2b T cells. The outcome of T cell activation by such liposomesin the absence of accessory cells was tested via flow cytometry and aT cell anergy assay.
Results. Provided the presence of external co-stimulation,MHC II/peptide liposomes were able to induce proliferation of the A2b T cellclone. More importantly incubation of these T cells withMHC II/peptide liposomes in the absence of co-stimulation did not induceproliferation, however, a MHC/peptide ligand-density dependent downregulation of the TCR was observed. Interestingly, when T cells afterincubation with the MHC II/peptide liposomes were restimulated withtheir specific antigen in the presence of professional APC, these cellswere anergic.
Conclusions. We propose MHC II/peptide liposomes as a novel meansto induce T cell anergy. The possibility to prepare ‘tailor-made’liposomal formulations may provide liposomes with an important advantagefor applications in immunotherapy.
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REFERENCES
J. D. Ashwell and R. H. Schwartz. T-cell recognition of antigen and the la molecule as a ternary complex. Nature 320:176–179 (1986).
A. Viola and A. Lanzavecchia. T cell activation determined by T cell receptor number and tunable thresholds. Science 273:104–106 (1996).
A. Grakoui, S. K. Bromley, C. Sumen, M. M. Davis, A. S. Shaw, P. M. Allen, and M. L. Dustin. The immunological synapse: A molecular machine controlling T cell activation. Science 285:221–227 (1999).
R. H. Schwartz. Models of T cell anergy: is there a common molecular mechanism? J. Exp. Med. 184:1–8 (1996).
L. S. Taams, A. J. M. L. van Rensen, M. C. M. Poelen, C. A. C. M. van Els, A. C. Besseling, J. P. A. Wagenaar, W. van Eden, and M. H. M. Wauben. Anergic T cells actively suppress T cell responses via the antigen presenting cell. Eur. J. Immunol. 28:2902–2912 (1998).
M. K. Jenkins and R. H. Schwartz. Antigen presentation by chemically modified splenocytes which induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165:302–319 (1987).
H. Quill and R. H. Schwartz. Stimulation of normal inducer T cell clones with antigen presented by purified la molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J. Immunol. 138:3704–3712 (1987).
M. W. Nicolle, B. Nag, S. D. Sharma, N. Willcox, A. Vincent, D. J. Ferguson, and J. Newsom-Davis. Specific tolerance to an acetylcholine receptor epitope induced in vitro in myasthenia gravis CD41 lymphocytes by soluble major histocompatibility complex class II-peptide complexes. J. Clin. Invest. 93:1361–1369 (1994).
J.-P. Abastado, Y.-C. Lone, A. Casrouge, G. Boulot, and P. Kourilsky. Dimerization of soluble major histocompatibility complex-peptide complexes is sufficient for activation of T cell hybridoma and induction of unresponsiveness. J. Exp. Med. 182:439–447 (1995).
B. Nag, T. Kendrick, S. Arimilli, S. C. T. Yu, and S. Sriram. Soluble MHC II-peptide complexes induce antigen-specific apoptosis in T cells. Cell. Immunol. 170:25–33 (1996).
N. Zavazava and M. Kronke. Soluble HLA class I molecules induce apoptosis in alloreactive cytotoxic T lymphocytes. Nature Med. 2:1005–1010 (1996).
S. Bourdoulous, E. Beraud, C. Le Page, A. Zamora, A. Ferry, D. Bernard, A. D. Strosberg, and P. O. Couraud. Anergy induction in encephalitogenic T cells by brain microvessel endothelial cells is inhibited by interleukin-1. Eur. J. Immunol. 25:1176–1183 (1995).
G. Lombardi, S. Sidhu, R. Batchelor, and R. Lechler. Anergic T cells as suppressor cells in vitro. Science 264:1587–1589 (1994).
S. Valitutti and A. Lanzavecchia. Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol. Today 18:299–304 (1997).
F. Crawford, H. Kozono, J. White, P. Marrack, and J. Kappler. Detection of antigen-specific T cells with multivalent soluble class II MHCcovalent peptide complexes. Immunity 8:675–682 (1998).
J. D. Altman, P. A. H. Moss, P. J. R. Goulder, D. H. Barouch, M. G. McHeyzer-Williams, J. I. Bell, A. J. McMichael, and M. M. Davis. Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96 (1996).
A. Chakrabarti, J. Matko, N. A. Rahman, B. G. Barisas, and M. Edidin. Self-association of class I major histocompatibility complex molecules in liposome and cell surface membranes. Biochemistry 31:7182–7189 (1992).
T. H. Watts, A. A. Brian, J. W. Kappler, P. Marrack, and H. M. McConnell. Antigen presentation by supported planar membranes containing affinity-purified I-Ad. Proc. Natl. Acad. Sci. USA 81:7564–7568 (1984).
A. J. M. L. van Rensen, M. H. M. Wauben, M. C. Grosfeld-Stulemeyer, W. van Eden, and D. J. A. Crommelin. Liposomes with incorporated MHC class II/peptide complexes as antigen-presenting vesicles for specific T cell activation. Pharm. Res. 16:198–204 (1999).
I. Joosten, M. H. Wauben, M. C. Holewijn, K. Reske, L. O. Pedersen, C. F. Roosenboom, E. J. Hensen, W. van Eden, and S. Buus. Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules. Int. Immunol. 6:751–759 (1994).
J. M. Steward and J. D. Young. Solid Phase Peptide Synthesis. Pierce Chemical, Rockford, IL, 1984.
L. S. Minamide and J. R. Bamburg. A filter paper dye-binding assay for quantitative determination of protein without interference from reducing agents or detergents. Anal Biochem 190:66–70 (1990).
J. Holoshitz, A. Matitiau, and I. R. Cohen. Arthritis induced in rats by cloned T lymphocytes responsive to Mycobacteria but not to collagen type II. J. Clin. Invest. 73:211–215 (1984).
L. Ding and E. M. Shevach. Activation of CD41 T cells by delivery of the B7 costimulatory signal on bystander antigen-presenting cells (trans-costimulation). Eur. J. Immunol. 24:859–866 (1994).
C. P. M. Broeren, M. H. M. Wauben, M. A. Lucassen, M. van Meurs, P. J. S. van Kooten, C. J. P. Boog, E. Claassen, and W. van Eden. Activated rat T cells synthesize and express functional major histocompatibility class II antigens. Immunology 84:193–201 (1995).
B. Nag, H. Garrett Wada, S. V. Deshpande, D. Passmore, T. Kendrick, S. D. Sharma, B. R. Clark, and H. M. McConnell. Stimulation of T cells by antigenic peptide complexes with isolated chains of major histocompatibility complex class II molecules. Proc. Natl. Acad. Sci. 90:1604–1608 (1993).
I. Vermes, C. Haanen, H. Steffens-Nakken, and C. Reutelingsperger. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J. Immunol. Meth. 184:39–51 (1995).
S. Valitutti, S. Muller, M. Cella, E. Padovan, and A. Lanzavecchia. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375:148–151 (1995).
M. Salio, S. Valitutti, and A. Lanzavecchia. Agonist-induced T cell receptor down-regulation: molecular requirements and dissociation from T cel activation. Eur. J. Immunol. 27:1769–1773 (1997).
G. Storm, and D. J. A. Crommelin. Liposomes: Quo vadis? PSTT 1:19–31 (1998).
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van Rensen, A.J.M.L., Taams, L.S., Grosfeld-Stulemeyer, M.C. et al. Induction of T Cell Anergy by Liposomes with Incorporated Major Histocompatibility Complex (MHC) II/Peptide Complexes. Pharm Res 17, 720–726 (2000). https://doi.org/10.1023/A:1007586400631
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DOI: https://doi.org/10.1023/A:1007586400631