Abstract
Bound antibodies can modulate antigen processing but it is not clear to what extent this affects antigen presentation. Here we show that presentation of T cell determinants in tetanus toxin can be either enhanced or suppressed as a direct consequence of antibody modulation of antigen processing in human B lymphoblastoid cells. Remarkably, a single bound antibody or its Fab fragment can simultaneously enhance the presentation of one T cell determinant by more than 10-fold while strongly suppressing the presentation of a different T cell determinant. Biochemical analysis demonstrates that both the suppressed and boosted determinants fall within an extended domain of antigen stabilized or "footprinted" by this antibody during proteolysis. These results demonstrate that bound antibodies can modulate the capture of peptides by class II major histocompatibility complex (MHC), thus manipulating the T cell response towards or away from particular determinants. Altered processing of protein-protein complexes leading to enhanced loading of class II MHC and substantially lowered threshold for T cell activation suggests a novel mechanism that might reveal "cryptic" self determinants.
Full Text
The Full Text of this article is available as a PDF (825.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Amigorena S., Drake J. R., Webster P., Mellman I. Transient accumulation of new class II MHC molecules in a novel endocytic compartment in B lymphocytes. Nature. 1994 May 12;369(6476):113–120. doi: 10.1038/369113a0. [DOI] [PubMed] [Google Scholar]
- Angus P. W., Mihaly G. W., Morgan D. J., Smallwood R. A. Oxygen dependence of omeprazole clearance and sulfone and sulfide metabolite formation in the isolated perfused rat liver. J Pharmacol Exp Ther. 1989 Sep;250(3):1043–1047. [PubMed] [Google Scholar]
- Barnett B. C., Graham C. M., Burt D. S., Skehel J. J., Thomas D. B. The immune response of BALB/c mice to influenza hemagglutinin: commonality of the B cell and T cell repertoires and their relevance to antigenic drift. Eur J Immunol. 1989 Mar;19(3):515–521. doi: 10.1002/eji.1830190316. [DOI] [PubMed] [Google Scholar]
- Berzofsky J. A. T-B reciprocity. An Ia-restricted epitope-specific circuit regulating T cell-B cell interaction and antibody specificity. Surv Immunol Res. 1983;2(3):223–229. doi: 10.1007/BF02918417. [DOI] [PubMed] [Google Scholar]
- Celada F., Sercarz E. E. Preferential pairing of T-B specificities in the same antigen: the concept of directional help. Vaccine. 1988 Apr;6(2):94–98. doi: 10.1016/s0264-410x(88)80006-9. [DOI] [PubMed] [Google Scholar]
- Cibotti R., Kanellopoulos J. M., Cabaniols J. P., Halle-Panenko O., Kosmatopoulos K., Sercarz E., Kourilsky P. Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):416–420. doi: 10.1073/pnas.89.1.416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davidson H. W., Watts C. Epitope-directed processing of specific antigen by B lymphocytes. J Cell Biol. 1989 Jul;109(1):85–92. doi: 10.1083/jcb.109.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davidson H. W., West M. A., Watts C. Endocytosis, intracellular trafficking, and processing of membrane IgG and monovalent antigen/membrane IgG complexes in B lymphocytes. J Immunol. 1990 Jun 1;144(11):4101–4109. [PubMed] [Google Scholar]
- Demotz S., Lanzavecchia A., Eisel U., Niemann H., Widmann C., Corradin G. Delineation of several DR-restricted tetanus toxin T cell epitopes. J Immunol. 1989 Jan 15;142(2):394–402. [PubMed] [Google Scholar]
- Dong X., Hamilton K. J., Satoh M., Wang J., Reeves W. H. Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen. J Exp Med. 1994 Apr 1;179(4):1243–1252. doi: 10.1084/jem.179.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eisel U., Jarausch W., Goretzki K., Henschen A., Engels J., Weller U., Hudel M., Habermann E., Niemann H. Tetanus toxin: primary structure, expression in E. coli, and homology with botulinum toxins. EMBO J. 1986 Oct;5(10):2495–2502. doi: 10.1002/j.1460-2075.1986.tb04527.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eisenberg R. J., Long D., Pereira L., Hampar B., Zweig M., Cohen G. H. Effect of monoclonal antibodies on limited proteolysis of native glycoprotein gD of herpes simplex virus type 1. J Virol. 1982 Feb;41(2):478–488. doi: 10.1128/jvi.41.2.478-488.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fairweather N. F., Lyness V. A. The complete nucleotide sequence of tetanus toxin. Nucleic Acids Res. 1986 Oct 10;14(19):7809–7812. doi: 10.1093/nar/14.19.7809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gammon G., Sercarz E. How some T cells escape tolerance induction. Nature. 1989 Nov 9;342(6246):183–185. doi: 10.1038/342183a0. [DOI] [PubMed] [Google Scholar]
- Harding C. V., Geuze H. J. Immunogenic peptides bind to class II MHC molecules in an early lysosomal compartment. J Immunol. 1993 Oct 15;151(8):3988–3998. [PubMed] [Google Scholar]
- Jemmerson R., Paterson Y. Mapping epitopes on a protein antigen by the proteolysis of antigen-antibody complexes. Science. 1986 May 23;232(4753):1001–1004. doi: 10.1126/science.2422757. [DOI] [PubMed] [Google Scholar]
- Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985 Apr 11;314(6011):537–539. doi: 10.1038/314537a0. [DOI] [PubMed] [Google Scholar]
- Lehmann P. V., Forsthuber T., Miller A., Sercarz E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
- Mamula M. J. The inability to process a self-peptide allows autoreactive T cells to escape tolerance. J Exp Med. 1993 Feb 1;177(2):567–571. doi: 10.1084/jem.177.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manca F., Fenoglio D., Kunkl A., Cambiaggi C., Sasso M., Celada F. Differential activation of T cell clones stimulated by macrophages exposed to antigen complexed with monoclonal antibodies. A possible influence of paratope specificity on the mode of antigen processing. J Immunol. 1988 May 1;140(9):2893–2898. [PubMed] [Google Scholar]
- Manca F., Kunkl A., Fenoglio D., Fowler A., Sercarz E., Celada F. Constraints in T-B cooperation related to epitope topology on E. coli beta-galactosidase. I. The fine specificity of T cells dictates the fine specificity of antibodies directed to conformation-dependent determinants. Eur J Immunol. 1985 Apr;15(4):345–350. doi: 10.1002/eji.1830150408. [DOI] [PubMed] [Google Scholar]
- Ozaki S., Berzofsky J. A. Antibody conjugates mimic specific B cell presentation of antigen: relationship between T and B cell specificity. J Immunol. 1987 Jun 15;138(12):4133–4142. [PubMed] [Google Scholar]
- Qiu Y., Xu X., Wandinger-Ness A., Dalke D. P., Pierce S. K. Separation of subcellular compartments containing distinct functional forms of MHC class II. J Cell Biol. 1994 May;125(3):595–605. doi: 10.1083/jcb.125.3.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schild H., Rötzschke O., Kalbacher H., Rammensee H. G. Limit of T cell tolerance to self proteins by peptide presentation. Science. 1990 Mar 30;247(4950):1587–1589. doi: 10.1126/science.2321019. [DOI] [PubMed] [Google Scholar]
- Sercarz E. E., Lehmann P. V., Ametani A., Benichou G., Miller A., Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729–766. doi: 10.1146/annurev.iy.11.040193.003501. [DOI] [PubMed] [Google Scholar]
- Tulp A., Verwoerd D., Dobberstein B., Ploegh H. L., Pieters J. Isolation and characterization of the intracellular MHC class II compartment. Nature. 1994 May 12;369(6476):120–126. doi: 10.1038/369120a0. [DOI] [PubMed] [Google Scholar]
- Watts C., Lanzavecchia A. Suppressive effect of antibody on processing of T cell epitopes. J Exp Med. 1993 Oct 1;178(4):1459–1463. doi: 10.1084/jem.178.4.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watts C., West M. A., Reid P. A., Davidson H. W. Processing of immunoglobulin-associated antigen in B lymphocytes. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):345–352. doi: 10.1101/sqb.1989.054.01.042. [DOI] [PubMed] [Google Scholar]
- West M. A., Lucocq J. M., Watts C. Antigen processing and class II MHC peptide-loading compartments in human B-lymphoblastoid cells. Nature. 1994 May 12;369(6476):147–151. doi: 10.1038/369147a0. [DOI] [PubMed] [Google Scholar]