Memory B cells at successive stages of differentiation. Affinity maturation and the role of IgD receptors (original) (raw)

Abstract

The following evidence, mainly presented here, suggests that IgD receptors play a crucial role in determining the potential for affinity maturation in memory B cell populations. IgD receptors are present on the first memory B cells to appear after priming. These memory cells give rise to more-mature memory cells that have lost their IgD receptors. The proportions of early (IgD(+)) and mature (IgD(-)) memory cells found in individual donors vary with time, priming conditions, and the availability of T cell help, and both populations frequently coexist for long periods of time. IgD(+) and IgD(-) memory cells carry IgG receptors and give rise to IgG responses with identical isotype representation in adoptive recipients. IgD(+) memory cells, however, always give rise to predominantly low-affinity antibody responses, whereas IgD(-) memory cells consistently generate responses of substantially higher average affinity. This affinity differential is maintained between early and mature memory populations in the same donor and does not appear to be a result of selective differentiation of higher-affinity IgD(+) memory cells into the IgD(-) memory pool. Thus, the selective forces responsible for affinity maturation appear to operate mainly in mature memory cell populations that have already lost IgD receptors; or, stated conversely, little or no selection towards high-affinity memory appears to occur among memory cells that retain IgD receptors. In discussing these findings, we suggest that the IgD receptors themselves are responsible for maintaining early memory populations at a lower average affinity than IgD(-) populations in the same animal. The IgD receptors, we argue, serve to increase the antigen-binding capacity of lower-affinity memory cells so that these cells can survive, expand, and differentiate (to IgD(-)) at antigen concentrations that select against expansion of low- affinity memory cells no longer carrying IgD receptors. Thus, when antigen is limiting, IgD(-) memory populations will be selectively expanded to higher average affinities, whereas coexisting IgD(+) populations will retain their initial affinity profile. This hypothesis suggests that mechanisms that regulate expression and loss of IgD receptors are central to the adaptability of the immune system in its response to invading pathogens. Two related roles can be envisioned for the IgD receptors in this regard. First, they extend the lower boundary of the affinity range of early memory cell populations induced by a given antigenic stimulus and therefore broaden the diversity of responses obtainable from these populations. Secondly, they support the persistence of low-affinity memory populations under conditions where antigen becomes limiting and eventually disappears. These persisting populations then serve as a diversely reactive reservoir from which mature memory populations can be drawn with higher affinities either for the original antigen or, more importantly, for related antigens that the animal may subsequently encounter. Thus the existence of IgD receptors on early memory cells maintains the full range of response diversity despite ongoing selective expansion of (mature) memory populations to produce antibodies with high combining affinities for individual antigens. The flexibility inherent in such an organizational system, we believe, could be expected to account for the evolutionary development of IgD receptors and the regulatory capabilities that support operation of the system.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Black S. J., Herzenberg L. A. B-cell influences on the induction of allotype suppressor T cells. J Exp Med. 1979 Jul 1;150(1):174–183. doi: 10.1084/jem.150.1.174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Black S. J., van der Loo W., Loken M. R., Herzenberg L. A. Expression of IgD by murine lymphocytes. Loss of surface IgD indicates maturation of memory B cells. J Exp Med. 1978 Apr 1;147(4):984–996. doi: 10.1084/jem.147.4.984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bourgois A., Abney E. R., Parkhouse R. M. Mouse immunoglobulin receptors on lymphocytes: identification of IgM and IgD molecules by tryptic cleavage and a postulated role for cell surface IgD. Eur J Immunol. 1977 Apr;7(4):210–213. doi: 10.1002/eji.1830070404. [DOI] [PubMed] [Google Scholar]
  4. Eichmann K., Falk I., Rajewsky K. Recognition of idiotypes in lymphocyte interactions. II. Antigen-independent cooperation between T and B lymphocytes that possess similar and complementary idiotypes. Eur J Immunol. 1978 Dec;8(12):853–857. doi: 10.1002/eji.1830081206. [DOI] [PubMed] [Google Scholar]
  5. Gershon R. K., Paul W. E. Effect of thymus-derived lymphocytes on amount and affinity of anti-hapten antibody. J Immunol. 1971 Mar;106(3):872–874. [PubMed] [Google Scholar]
  6. Herzenberg L. A., Herzenberg L. A. Short-term and chronic allotype suppression in mice. Contemp Top Immunobiol. 1974;3:41–75. doi: 10.1007/978-1-4684-3045-5_2. [DOI] [PubMed] [Google Scholar]
  7. Herzenberg L. A., Okumura K., Cantor H., Sato V. L., Shen F. W., Boyse E. A., Herzenberg L. A. T-cell regulation of antibody responses: demonstration of allotype-specific helper T cells and their specific removal by suppressor T cells. J Exp Med. 1976 Aug 1;144(2):330–344. doi: 10.1084/jem.144.2.330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Herzenberg L. A., Okumura K., Metzler C. M. Regulation of immunoglobulin and antibody production by allotype suppressor T cells in mice. Transplant Rev. 1975;27:57–83. doi: 10.1111/j.1600-065x.1975.tb00184.x. [DOI] [PubMed] [Google Scholar]
  9. Johnston M. F., Barisas B. G., Sturtevant J. M. Thermodynamics of hapten binding to MOPC 315 and MOPC 460 mouse myeloma proteins. Biochemistry. 1974 Jan 15;13(2):390–396. doi: 10.1021/bi00699a026. [DOI] [PubMed] [Google Scholar]
  10. Kettman J. R., Cambier J. C., Uhr J. W., Ligler F., Vitetta E. S. The role of receptor IgM and IgD in determining triggering and induction of tolerance in murine B cells. Immunol Rev. 1979;43:69–95. doi: 10.1111/j.1600-065x.1979.tb00418.x. [DOI] [PubMed] [Google Scholar]
  11. Okumura K., Metzler C. M., Tsu T. T., Herzenberg L. A., Herzenberg L. A. Two stages of B-cell memory development with different T-cell requirements. J Exp Med. 1976 Aug 1;144(2):345–357. doi: 10.1084/jem.144.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Paul W. E., Siskind G. W., Benacerraf B., Ovary Z. Secondary antibody responses in haptenic systems: cell population selection by antigen. J Immunol. 1967 Oct;99(4):760–770. [PubMed] [Google Scholar]
  13. Pecht I., Givol D., Sela M. Dynamics of hapten-antibody interaction. Studies on a myeloma protein with anti-2,4-dinitrophenyl specificity. J Mol Biol. 1972 Jul 21;68(2):241–247. doi: 10.1016/0022-2836(72)90211-2. [DOI] [PubMed] [Google Scholar]
  14. Woodland R., Cantor H. Idiotype-specific T helper cells are required to induce idiotype-positive B memory cells to secrete antibody. Eur J Immunol. 1978 Aug;8(8):600–606. doi: 10.1002/eji.1830080812. [DOI] [PubMed] [Google Scholar]