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. 1994 Jan 1;179(1):249–258. doi: 10.1084/jem.179.1.249

Tolerogenicity of resting and activated B cells

PMCID: PMC2191345  PMID: 7505799

Abstract

Antigen presentation by resting splenic B cells has been shown previously to induce T helper 1 cell (Th1) anergy. In contrast to expectations, it was found here that B cells treated with F(ab')2 goat anti-mouse immunoglobulin (IgM) for 24 or 48 h also presented antigen (Ag) to Th1 cells in a manner that induced dramatic Ag-specific proliferative inactivation. The tolerogenicity of the anti-Ig-treated B cells was consistent with the observation that these B cells were only slightly more efficient than resting B cells in stimulating human gamma globulin (HGG)-induced proliferation of HGG-specific Th1 cells in primary cultures. The activated B cells were, however, more efficient than resting B cells in stimulating a primary mixed leukocyte reaction, and exhibited increased expression of major histocompatibility complex class II molecules, RL388 Ag and transferrin receptor. In addition, unlike resting B cells, which expressed little detectable B7, anti-Ig- treated B cells expressed high levels of B7. The functional capacity of the B7 expressed on the activated B cells was demonstrated by the fact that the Ag-presenting capacity of these B cells was inhibited by the addition to culture of CTLA4Ig, a soluble receptor for B7. It is unlikely that the tolerogenicity of the activated B cells was due to an inability of the Th1 cells to respond to B7 signals; the Th1 clones used in the experiments, unlike the Th2 clones tested, expressed CD28, the ligand for B7. In addition, anti-CD28 monoclonal antibody inhibited the induction of Th1 cell anergy when added to cultures of Th1 cells and Ag-pulsed fixed antigen-presenting cells. Taken together, the results indicate that B cells, even when activated, do not satisfy the costimulatory requirements of the Th1 cells used here, and therefore can present Ag in a tolerogenic fashion to Th1 cells. The costimulator deficiency of activated B cells may reflect an inadequacy in the level of B7 expressed or a lack of some other molecule.

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Selected References

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  1. Ashwell J. D., Jenkins M. K., Schwartz R. H. Effect of gamma radiation on resting B lymphocytes. II. Functional characterization of the antigen-presentation defect. J Immunol. 1988 Oct 15;141(8):2536–2544. [PubMed] [Google Scholar]
  2. Azuma M., Cayabyab M., Buck D., Phillips J. H., Lanier L. L. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J Exp Med. 1992 Feb 1;175(2):353–360. doi: 10.1084/jem.175.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Azuma M., Yssel H., Phillips J. H., Spits H., Lanier L. L. Functional expression of B7/BB1 on activated T lymphocytes. J Exp Med. 1993 Mar 1;177(3):845–850. doi: 10.1084/jem.177.3.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baumhüter S., Bron C., Corradin G. Different antigen-presenting cells differ in their capacity to induce lymphokine production and proliferation of an apo-cytochrome c-specific T cell clone. J Immunol. 1985 Aug;135(2):989–994. [PubMed] [Google Scholar]
  5. Brunet J. F., Denizot F., Luciani M. F., Roux-Dosseto M., Suzan M., Mattei M. G., Golstein P. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987 Jul 16;328(6127):267–270. doi: 10.1038/328267a0. [DOI] [PubMed] [Google Scholar]
  6. Casten L. A., Lakey E. K., Jelachich M. L., Margoliash E., Pierce S. K. Anti-immunoglobulin augments the B-cell antigen-presentation function independently of internalization of receptor-antigen complex. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5890–5894. doi: 10.1073/pnas.82.17.5890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ernst D. N., McQuitty D. N., Weigle W. O., Hobbs M. V. Expression of membrane activation antigens on murine B lymphocytes stimulated with lipopolysaccharide. Cell Immunol. 1988 Jun;114(1):161–173. doi: 10.1016/0008-8749(88)90263-8. [DOI] [PubMed] [Google Scholar]
  8. Eynon E. E., Parker D. C. Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med. 1992 Jan 1;175(1):131–138. doi: 10.1084/jem.175.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fabry Z., Sandor M., Gajewski T. F., Herlein J. A., Waldschmidt M. M., Lynch R. G., Hart M. N. Differential activation of Th1 and Th2 CD4+ cells by murine brain microvessel endothelial cells and smooth muscle/pericytes. J Immunol. 1993 Jul 1;151(1):38–47. [PubMed] [Google Scholar]
  10. Freedman A. S., Freeman G. J., Rhynhart K., Nadler L. M. Selective induction of B7/BB-1 on interferon-gamma stimulated monocytes: a potential mechanism for amplification of T cell activation through the CD28 pathway. Cell Immunol. 1991 Oct 15;137(2):429–437. doi: 10.1016/0008-8749(91)90091-o. [DOI] [PubMed] [Google Scholar]
  11. Freeman G. J., Freedman A. S., Segil J. M., Lee G., Whitman J. F., Nadler L. M. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714–2722. [PubMed] [Google Scholar]
  12. Freeman G. J., Gribben J. G., Boussiotis V. A., Ng J. W., Restivo V. A., Jr, Lombard L. A., Gray G. S., Nadler L. M. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993 Nov 5;262(5135):909–911. doi: 10.1126/science.7694363. [DOI] [PubMed] [Google Scholar]
  13. Fuchs E. J., Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992 Nov 13;258(5085):1156–1159. doi: 10.1126/science.1439825. [DOI] [PubMed] [Google Scholar]
  14. Gajewski T. F., Pinnas M., Wong T., Fitch F. W. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations. J Immunol. 1991 Mar 15;146(6):1750–1758. [PubMed] [Google Scholar]
  15. Galvin F., Freeman G. J., Razi-Wolf Z., Hall W., Jr, Benacerraf B., Nadler L., Reiser H. Murine B7 antigen provides a sufficient costimulatory signal for antigen-specific and MHC-restricted T cell activation. J Immunol. 1992 Dec 15;149(12):3802–3808. [PubMed] [Google Scholar]
  16. Gilbert K. M., Hoang K. D., Weigle W. O. Th1 and Th2 clones differ in their response to a tolerogenic signal. J Immunol. 1990 Mar 15;144(6):2063–2071. [PubMed] [Google Scholar]
  17. Gilbert K. M., Weigle W. O. B cell presentation of a tolerogenic signal to Th clones. Cell Immunol. 1992 Jan;139(1):58–71. doi: 10.1016/0008-8749(92)90099-b. [DOI] [PubMed] [Google Scholar]
  18. Gosselin E. J., Tony H. P., Parker D. C. Characterization of antigen processing and presentation by resting B lymphocytes. J Immunol. 1988 Mar 1;140(5):1408–1413. [PubMed] [Google Scholar]
  19. Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
  20. Hathcock K. S., Laszlo G., Dickler H. B., Bradshaw J., Linsley P., Hodes R. J. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993 Nov 5;262(5135):905–907. doi: 10.1126/science.7694361. [DOI] [PubMed] [Google Scholar]
  21. Hawrylowicz C. M., Unanue E. R. Regulation of antigen-presentation-I. IFN-gamma induces antigen-presenting properties on B cells. J Immunol. 1988 Dec 15;141(12):4083–4088. [PubMed] [Google Scholar]
  22. Hori S., Sato S., Kitagawa S., Azuma T., Kokudo S., Hamaoka T., Fujiwara H. Tolerance induction of allo-class II H-2 antigen-reactive L3T4+ helper T cells and prolonged survival of the corresponding class II H-2-disparate skin graft. J Immunol. 1989 Sep 1;143(5):1447–1452. [PubMed] [Google Scholar]
  23. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jenkins M. K., Taylor P. S., Norton S. D., Urdahl K. B. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991 Oct 15;147(8):2461–2466. [PubMed] [Google Scholar]
  25. June C. H., Ledbetter J. A., Linsley P. S., Thompson C. B. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990 Jun;11(6):211–216. doi: 10.1016/0167-5699(90)90085-n. [DOI] [PubMed] [Google Scholar]
  26. Kakiuchi T., Chesnut R. W., Grey H. M. B cells as antigen-presenting cells: the requirement for B cell activation. J Immunol. 1983 Jul;131(1):109–114. [PubMed] [Google Scholar]
  27. Kakiuchi T., Mizuguchi J., Nariuchi H. Molecular analysis of the dissociation between IL-2 production and proliferation in a response of a T cell clone to the antigen presented by B cells. J Immunol. 1988 Nov 15;141(10):3278–3284. [PubMed] [Google Scholar]
  28. Klaus G. G., Hawrylowicz C. M., Carter C. J. Activation and proliferation signals in mouse B cells. VI. Anti-Ig antibodies induce dose-dependent cell cycle progression in B cells. Immunology. 1985 Jul;55(3):411–418. [PMC free article] [PubMed] [Google Scholar]
  29. Krieger J. I., Grammer S. F., Grey H. M., Chesnut R. W. Antigen presentation by splenic B cells: resting B cells are ineffective, whereas activated B cells are effective accessory cells for T cell responses. J Immunol. 1985 Nov;135(5):2937–2945. [PubMed] [Google Scholar]
  30. Langhoff E., Steinman R. M. Clonal expansion of human T lymphocytes initiated by dendritic cells. J Exp Med. 1989 Jan 1;169(1):315–320. doi: 10.1084/jem.169.1.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Larsen C. P., Ritchie S. C., Pearson T. C., Linsley P. S., Lowry R. P. Functional expression of the costimulatory molecule, B7/BB1, on murine dendritic cell populations. J Exp Med. 1992 Oct 1;176(4):1215–1220. doi: 10.1084/jem.176.4.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ledbetter J. A., Shu G., Gallagher M., Clark E. A. Augmentation of normal and malignant B cell proliferation by monoclonal antibody to the B cell-specific antigen BP50 (CDW40). J Immunol. 1987 Feb 1;138(3):788–794. [PubMed] [Google Scholar]
  33. Lenschow D. J., Zeng Y., Thistlethwaite J. R., Montag A., Brady W., Gibson M. G., Linsley P. S., Bluestone J. A. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992 Aug 7;257(5071):789–792. doi: 10.1126/science.1323143. [DOI] [PubMed] [Google Scholar]
  34. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Linsley P. S., Brady W., Urnes M., Grosmaire L. S., Damle N. K., Ledbetter J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561–569. doi: 10.1084/jem.174.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Linsley P. S., Clark E. A., Ledbetter J. A. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5031–5035. doi: 10.1073/pnas.87.13.5031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Monroe J. G., Cambier J. C. Level of mIa expression on mitogen-stimulated murine B lymphocytes is dependent on position in cell cycle. J Immunol. 1983 Feb;130(2):626–631. [PubMed] [Google Scholar]
  38. Muñoz E., Zubiaga A., Olson D., Huber B. T. Control of lymphokine expression in T helper 2 cells. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9461–9464. doi: 10.1073/pnas.86.23.9461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Parks D. E., Doyle M. V., Weigle W. O. Induction and mode of action of suppressor cells generated against human gamma globulin. I. An immunologic unresponsive state devoid of demonstrable suppressor cells. J Exp Med. 1978 Sep 1;148(3):625–638. doi: 10.1084/jem.148.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Taira S., Kato T., Yamamoto K., Inoue T., Nariuchi H. Differential requirement for humoral factors for IL-2R expression of murine T cell subsets, Th1, Th2, and CD8Th clones. Cell Immunol. 1993 Mar;147(1):41–50. doi: 10.1006/cimm.1993.1046. [DOI] [PubMed] [Google Scholar]
  42. Tan P., Anasetti C., Hansen J. A., Melrose J., Brunvand M., Bradshaw J., Ledbetter J. A., Linsley P. S. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med. 1993 Jan 1;177(1):165–173. doi: 10.1084/jem.177.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Thompson C. B., Lindsten T., Ledbetter J. A., Kunkel S. L., Young H. A., Emerson S. G., Leiden J. M., June C. H. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333–1337. doi: 10.1073/pnas.86.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Thorley-Lawson D. A., Nadler L. M., Bhan A. K., Schooley R. T. BLAST-2 [EBVCS], an early cell surface marker of human B cell activation, is superinduced by Epstein Barr virus. J Immunol. 1985 May;134(5):3007–3012. [PubMed] [Google Scholar]
  45. Waldmann T. A., Goldman C. K., Robb R. J., Depper J. M., Leonard W. J., Sharrow S. O., Bongiovanni K. F., Korsmeyer S. J., Greene W. C. Expression of interleukin 2 receptors on activated human B cells. J Exp Med. 1984 Nov 1;160(5):1450–1466. doi: 10.1084/jem.160.5.1450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Warner G. L., Scott D. W. A polyclonal model for B cell tolerance. I. Fc-dependent and Fc-independent induction of nonresponsiveness by pretreatment of normal splenic B cells with anti-Ig. J Immunol. 1991 Apr 1;146(7):2185–2191. [PubMed] [Google Scholar]
  47. Weaver C. T., Hawrylowicz C. M., Unanue E. R. T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8181–8185. doi: 10.1073/pnas.85.21.8181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Williams I. R., Unanue E. R. Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody. J Immunol. 1990 Jul 1;145(1):85–93. [PubMed] [Google Scholar]
  49. Yokochi T., Holly R. D., Clark E. A. B lymphoblast antigen (BB-1) expressed on Epstein-Barr virus-activated B cell blasts, B lymphoblastoid cell lines, and Burkitt's lymphomas. J Immunol. 1982 Feb;128(2):823–827. [PubMed] [Google Scholar]

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