Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1997 Jun 15;16(12):3553–3562. doi: 10.1093/emboj/16.12.3553

Acceleration of intracellular targeting of antigen by the B-cell antigen receptor: importance depends on the nature of the antigen-antibody interaction.

V R Aluvihare 1, A A Khamlichi 1, G T Williams 1, L Adorini 1, M S Neuberger 1
PMCID: PMC1169980  PMID: 9218797

Abstract

The B-cell antigen receptor (BCR) internalizes bound antigen such that antigen-derived peptides become associated with emigrating major histocompatibility complex (MHC) class II molecules for presentation to T cells. Experiments with B-cell transfectants reveal that BCR confers a specificity of intracellular targeting since chimeric antigen receptors which internalize antigen by virtue of a heterologous cytoplasmic domain do not necessarily give rise to presentation. In contrast, however, previous studies have shown that antigen binding to irrelevant cell surface molecules (e.g. transferrin receptor, MHC class I) can ultimately lead to presentation. The solution to this paradox appears to be that the intracellular targeting by BCR actually reflects an acceleration of antigen delivery. Depending on the nature of the BCR-antigen interaction, this accelerated targeting can be essential in determining whether or not internalization leads to significant presentation. Physiologically, the accelerated delivery of antigen by BCR could prove of particular importance early in the immune response when antigen-BCR interaction is likely to be poor.

Full Text

The Full Text of this article is available as a PDF (624.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adorini L., Guéry J. C., Fuchs S., Ortiz-Navarrete V., Hämmerling G. J., Momburg F. Processing of endogenously synthesized hen egg-white lysozyme retained in the endoplasmic reticulum or in secretory form gives rise to a similar but not identical set of epitopes recognized by class II-restricted T cells. J Immunol. 1993 Oct 1;151(7):3576–3586. [PubMed] [Google Scholar]
  2. 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]
  3. Amit A. G., Mariuzza R. A., Phillips S. E., Poljak R. J. Three-dimensional structure of an antigen-antibody complex at 2.8 A resolution. Science. 1986 Aug 15;233(4765):747–753. doi: 10.1126/science.2426778. [DOI] [PubMed] [Google Scholar]
  4. Bonnerot C., Lankar D., Hanau D., Spehner D., Davoust J., Salamero J., Fridman W. H. Role of B cell receptor Ig alpha and Ig beta subunits in MHC class II-restricted antigen presentation. Immunity. 1995 Sep;3(3):335–347. doi: 10.1016/1074-7613(95)90118-3. [DOI] [PubMed] [Google Scholar]
  5. Bretscher M. S. Circulating integrins: alpha 5 beta 1, alpha 6 beta 4 and Mac-1, but not alpha 3 beta 1, alpha 4 beta 1 or LFA-1. EMBO J. 1992 Feb;11(2):405–410. doi: 10.1002/j.1460-2075.1992.tb05068.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Castellino F., Germain R. N. Extensive trafficking of MHC class II-invariant chain complexes in the endocytic pathway and appearance of peptide-loaded class II in multiple compartments. Immunity. 1995 Jan;2(1):73–88. doi: 10.1016/1074-7613(95)90080-2. [DOI] [PubMed] [Google Scholar]
  7. Casten L. A., Pierce S. K. Receptor-mediated B cell antigen processing. Increased antigenicity of a globular protein covalently coupled to antibodies specific for B cell surface structures. J Immunol. 1988 Jan 15;140(2):404–410. [PubMed] [Google Scholar]
  8. Chesnut R. W., Grey H. M. Studies on the capacity of B cells to serve as antigen-presenting cells. J Immunol. 1981 Mar;126(3):1075–1079. [PubMed] [Google Scholar]
  9. Fields B. A., Goldbaum F. A., Ysern X., Poljak R. J., Mariuzza R. A. Molecular basis of antigen mimicry by an anti-idiotope. Nature. 1995 Apr 20;374(6524):739–742. doi: 10.1038/374739a0. [DOI] [PubMed] [Google Scholar]
  10. Janeway C. A., Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994 Jan 28;76(2):275–285. doi: 10.1016/0092-8674(94)90335-2. [DOI] [PubMed] [Google Scholar]
  11. Kappler J., White J., Wegmann D., Mustain E., Marrack P. Antigen presentation by Ia+ B cell hybridomas to H-2-restricted T cell hybridomas. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3604–3607. doi: 10.1073/pnas.79.11.3604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kim K. J., Kanellopoulos-Langevin C., Merwin R. M., Sachs D. H., Asofsky R. Establishment and characterization of BALB/c lymphoma lines with B cell properties. J Immunol. 1979 Feb;122(2):549–554. [PubMed] [Google Scholar]
  13. 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]
  14. Lanzavecchia A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu Rev Immunol. 1990;8:773–793. doi: 10.1146/annurev.iy.08.040190.004013. [DOI] [PubMed] [Google Scholar]
  15. McCafferty J., Griffiths A. D., Winter G., Chiswell D. J. Phage antibodies: filamentous phage displaying antibody variable domains. Nature. 1990 Dec 6;348(6301):552–554. doi: 10.1038/348552a0. [DOI] [PubMed] [Google Scholar]
  16. McCoy K. L., Noone M., Inman J. K., Stutzman R. Exogenous antigens internalized through transferrin receptors activate CD4+ T cells. J Immunol. 1993 Mar 1;150(5):1691–1704. [PubMed] [Google Scholar]
  17. Mitchell R. N., Barnes K. A., Grupp S. A., Sanchez M., Misulovin Z., Nussenzweig M. C., Abbas A. K. Intracellular targeting of antigens internalized by membrane immunoglobulin in B lymphocytes. J Exp Med. 1995 May 1;181(5):1705–1714. doi: 10.1084/jem.181.5.1705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  19. Niebling W. L., Pierce S. K. Antigen entry into early endosomes is insufficient for MHC class II processing. J Immunol. 1993 Apr 1;150(7):2687–2697. [PubMed] [Google Scholar]
  20. Parikh V. S., Bishop G. A., Liu K. J., Do B. T., Ghosh M. R., Kim B. S., Tucker P. W. Differential structure-function requirements of the transmembranal domain of the B cell antigen receptor. J Exp Med. 1992 Oct 1;176(4):1025–1031. doi: 10.1084/jem.176.4.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Patel K. J., Neuberger M. S. Antigen presentation by the B cell antigen receptor is driven by the alpha/beta sheath and occurs independently of its cytoplasmic tyrosines. Cell. 1993 Sep 10;74(5):939–946. doi: 10.1016/0092-8674(93)90473-4. [DOI] [PubMed] [Google Scholar]
  22. Pinet V., Vergelli M., Martin R., Bakke O., Long E. O. Antigen presentation mediated by recycling of surface HLA-DR molecules. Nature. 1995 Jun 15;375(6532):603–606. doi: 10.1038/375603a0. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Reth M., Imanishi-Kari T., Rajewsky K. Analysis of the repertoire of anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies in C 57 BL/6 mice by cell fusion. II. Characterization of idiotopes by monoclonal anti-idiotope antibodies. Eur J Immunol. 1979 Dec;9(12):1004–1013. doi: 10.1002/eji.1830091216. [DOI] [PubMed] [Google Scholar]
  25. Shaw A. C., Mitchell R. N., Weaver Y. K., Campos-Torres J., Abbas A. K., Leder P. Mutations of immunoglobulin transmembrane and cytoplasmic domains: effects on intracellular signaling and antigen presentation. Cell. 1990 Oct 19;63(2):381–392. doi: 10.1016/0092-8674(90)90171-a. [DOI] [PubMed] [Google Scholar]
  26. Snider D. P., Segal D. M. Efficiency of antigen presentation after antigen targeting to surface IgD, IgM, MHC, Fc gamma RII, and B220 molecules on murine splenic B cells. J Immunol. 1989 Jul 1;143(1):59–65. [PubMed] [Google Scholar]
  27. Song W., Cho H., Cheng P., Pierce S. K. Entry of B cell antigen receptor and antigen into class II peptide-loading compartment is independent of receptor cross-linking. J Immunol. 1995 Nov 1;155(9):4255–4263. [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. Williams G. T., Venkitaraman A. R., Gilmore D. J., Neuberger M. S. The sequence of the mu transmembrane segment determines the tissue specificity of the transport of immunoglobulin M to the cell surface. J Exp Med. 1990 Mar 1;171(3):947–952. doi: 10.1084/jem.171.3.947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Yélamos J., Klix N., Goyenechea B., Lozano F., Chui Y. L., González Fernández A., Pannell R., Neuberger M. S., Milstein C. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature. 1995 Jul 20;376(6537):225–229. doi: 10.1038/376225a0. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES