Abstract
T-lymphocyte recognition of antigen either on antigen-presenting cells (APC) necessary for the generation of an immune response or on target cells during the effector phase of a cellular immune response requires expression of HLA molecules. Although immune mechanisms operate in many disease processes of the central nervous system (CNS), cells of the CNS generally express low levels of HLA molecules. In this study, the potential for upregulation of HLA molecules on adult human glial cells was examined. Moreover, the functional implication of this upregulation was assessed by the capacity of glial cells to process and present target antigens to HLA class I-restricted influenza-specific and class II-restrict myelin basic protein (MBP)-specific CTL lines. Glial cells cultured from adult human surgical brain specimens or cells from established glioblastoma multiforme cell lines were studied. Lysis by antigen-specific CTLs was dependent on treatment of the target cell with interferon-γ. The lysis was HLA restricted and antigen specific. The results indicate that adult human glial cells can process and present antigen to HLA-restricted CTLs but require the upregulation of HLA molecules. These findings have implications for infectious and autoimmune diseases of the CNS.
Keywords: Antigen presentation, Astrocyte, Microglia, Myelin basic protein
References
- Biddison W.E. The role of the major histocompatibility complex in cytotoxic T-cell responses to virus infected cells. J. Clin. Immunol. 1982;2:1–9. doi: 10.1007/BF00915971. [DOI] [PubMed] [Google Scholar]
- Bigner D.D., Bigner S.H., Ponten J., Westermark B., Mahaley M.S., Ruoslahti E., Herschman H., Eng L.F., Wikstrand C.F. Heterogeneity of genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas. J. Neuropathol. Exp. Neurol. 1981;40:201–229. doi: 10.1097/00005072-198105000-00001. [DOI] [PubMed] [Google Scholar]
- Caspori A.A., Katz S.I. Induction and functional characterization of class II MHC (Ia) antigens on murine keratinocytes. J. Immunol. 1988;140:2956–2963. [PubMed] [Google Scholar]
- Cowan E.P., Jelachich M.L., Coligan J.E., Biddison W.E. Vol. 84. 1987. Site directed mutagenesis of an HLA-A3 gene identifies amino acid 152 as crucial for major histocompatibility complex-restricted and alloreactive cytotoxic T-lymphocyte recognition; pp. 5014–5018. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dhib-Jalbut S., Jacobson S., McFarlin D.E., McFarland H.F. Impaired human leukocyte antigen-restricted measles virus-specific cytotoxic T-cell response in subacute sclerosing panencephalitis. Ann. Neurol. 1989;25:272–280. doi: 10.1002/ana.410250311. [DOI] [PubMed] [Google Scholar]
- Fontana A., Fierz W., Wekerle H. Astrocytes present myelin basic protein to encephalitogenic T cell lines. Nature. 1984;307:273–276. doi: 10.1038/307273a0. [DOI] [PubMed] [Google Scholar]
- Fontana A., Frei K., Bodmer S., Hofer E. Immune-mediated encephalitis: on the role of antigen-presenting cells in brain tissue. Immunol. Rev. 1987;100:183–201. doi: 10.1111/j.1600-065X.1987.tb00532.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Frohman E., Van den Noort S., Gupta S. Astrocytes and intracerebral immune responses. J. Clin. Immunol. 1989;9:1–9. doi: 10.1007/BF00917121. [DOI] [PubMed] [Google Scholar]
- Geppert T.D., Lipsky P.E. Antigen presentation by interferon-γ-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression. J. Immunol. 1985;135:3750–3762. [PubMed] [Google Scholar]
- Grenier Y., Ruijs T.C.G., Robitaille Y., Olivier A., Antel J.P. Immunohistochemical studies of adult human glial cells. J. Neuroimmunol. 1989;21:103–115. doi: 10.1016/0165-5728(89)90166-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hayes G.M., Woodroffe M.N., Cuzner M.L. Microglia are the major cell type expressing MHC class II in human white matter. J. Neurol. Sci. 1987;80:25–37. doi: 10.1016/0022-510x(87)90218-8. [DOI] [PubMed] [Google Scholar]
- Hirayama M., Yokochi T., Shimokata K., Iida M., Fujiki N. Induction of human leukocyte antigen-A, B, C, and DR on cultured human oligodendrocytes and astrocytes by human gamma-interferon. Neurosci. Lett. 1986;72:369–374. doi: 10.1016/0304-3940(86)90543-4. [DOI] [PubMed] [Google Scholar]
- Massa P.T., Dorries R., ter Meulen V. Viral particles induce Ia antigen expression on astrocytes. Nature. 1986;320:543–546. doi: 10.1038/320543a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Massa P.T., Brinkman R., ter Meulen V. Inducibility of Ia antigen on astrocytes by murine coronavirus JHM is rat strain dependent. J. Exp. Med. 1987;166:259–264. doi: 10.1084/jem.166.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCarron R.M., Kempski O., Spatz M., McFarlin D.E. Presentation of myelin basic protein by murine cerebral vascular endothelial cells. J. Immunol. 1985;134:3100–3103. [PubMed] [Google Scholar]
- Mokhtarian F., McFarlin D.E., Raine C.S. Adoptive transfer of myelin basic protein-sensitized T cells produces chronic-relapsing demyelinating disease in mice. Nature. 1984;309:356–358. doi: 10.1038/309356a0. [DOI] [PubMed] [Google Scholar]
- Nuchtern J.G., Bonifacio J.S., Biddison W.E., Klausner R.D. Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation. Nature. 1989;339:223–226. doi: 10.1038/339223a0. [DOI] [PubMed] [Google Scholar]
- Oldstone M.B.A., Blount P.J., Southern P.J., Lampert P.W. Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system. Nature. 1986;321:239–243. doi: 10.1038/321239a0. [DOI] [PubMed] [Google Scholar]
- Poltorak M., Freed W. Immunological reactions induced by intracerebral transplantation: evidence that host microglia but not astroglia are antigen-presenting cells. Exp. Neurol. 1989;103:222–233. doi: 10.1016/0014-4886(89)90046-0. [DOI] [PubMed] [Google Scholar]
- Sun D., Wekerle H. Ia-restricted encephalitogenic T lymphocytes mediating EAE lyse autoantigen-presenting astrocytes. Nature. 1986;320:70–72. doi: 10.1038/320070a0. [DOI] [PubMed] [Google Scholar]
- Sun D., Meyermann R., Wekerle H. Cytotoxic T cells in autoimmune disease of the central nervous system. Ann. N.Y. Acad. Sci. 1988;532:221–229. doi: 10.1111/j.1749-6632.1988.tb36341.x. [DOI] [PubMed] [Google Scholar]
- Traugott U. Multiple sclerosis: relevance of class I and class II MHC-expressing cells to lesion development. J. Neuroimmunol. 1987;16:283–302. doi: 10.1016/0165-5728(87)90082-8. [DOI] [PubMed] [Google Scholar]
- Wikstrand C.J., Grahmann F.C., McComb R.D., Bigner D.D. Antigenic heterogeneity of human anaplastic gliomas and glioma-derived cell lines defined by monoclonal antibodies. J. Neuropathol. Exp. Neurol. 1985;44:229–241. doi: 10.1097/00005072-198505000-00002. [DOI] [PubMed] [Google Scholar]
- Williams K., Hart D., Fabre J., Morris P. Distribution and quantitation of HLA-A, B, C, and DR (Ia) antigens on human kidney and other tissues. Transplantation (Baltimore) 1980;29:274–279. doi: 10.1097/00007890-198004000-00002. [DOI] [PubMed] [Google Scholar]
- Wong G.M.W., Barlett P.F., Clark-Lewis I., Battye F., Schrader J.W. Inducible expression of H-2 and Ia antigens on brain cells. Nature. 1984;310:688–691. doi: 10.1038/310688a0. [DOI] [PubMed] [Google Scholar]
- Zinkernagel R.M., Doherty P.C. Restriction of in vivo T-cell mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogenic system. Nature. 1974;248:701–770. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]