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. 1996 Oct 1;93(20):11019–11024. doi: 10.1073/pnas.93.20.11019

A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+ CD3- cells to colonize lymph nodes.

R E Mebius 1, P R Streeter 1, S Michie 1, E C Butcher 1, I L Weissman 1
PMCID: PMC38276  PMID: 8855301

Abstract

IN adult mice, the dominant adhesion molecules involved in homing to lymph nodes are L-selectin homing receptors on lymphocytes and the peripheral lymph node addressins on specialized high endothelial venules. Here we show that, from fetal life through the first 24 hr of life, the dominant adhesion molecules are the mucosal addressin MAdCAM-1 on lymph node high endothelial venules and its counterreceptor, the Peyer's patch homing receptor, integrin alpha 4 beta 7 on circulating cells. Before birth, 40-70% of peripheral blood leukocytes are L-selectin-positive, while only 1-2% expresses alpha 4 beta 7. However, the fetal lymph nodes preferentially attract alpha 4 beta 7-expressing cells, and this can be blocked by fetal administration of anti-MAdCAM-1 antibodies. During fetal and early neonatal life, when only MAdCAM-1 is expressed on high endothelial venules, an unusual subset of CD4 + CD3- cells, exclusively expressing alpha 4 beta 7 as homing receptors, enters the lymph nodes. Beginning 24 hr after birth a developmental switch occurs, and the peripheral node addressins are upregulated on high endothelial venules in peripheral and mesenteric lymph nodes. This switch in addressin expression facilitates tissue-selective lymphocyte migration and mediates a sequential entry of different cell populations into the lymph nodes.

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Selected References

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

  1. Andrew D. P., Berlin C., Honda S., Yoshino T., Hamann A., Holzmann B., Kilshaw P. J., Butcher E. C. Distinct but overlapping epitopes are involved in alpha 4 beta 7-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation. J Immunol. 1994 Nov 1;153(9):3847–3861. [PubMed] [Google Scholar]
  2. Arbonés M. L., Ord D. C., Ley K., Ratech H., Maynard-Curry C., Otten G., Capon D. J., Tedder T. F. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity. 1994 Jul;1(4):247–260. doi: 10.1016/1074-7613(94)90076-0. [DOI] [PubMed] [Google Scholar]
  3. Banks T. A., Rouse B. T., Kerley M. K., Blair P. J., Godfrey V. L., Kuklin N. A., Bouley D. M., Thomas J., Kanangat S., Mucenski M. L. Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol. 1995 Aug 15;155(4):1685–1693. [PubMed] [Google Scholar]
  4. Bargatze R. F., Jutila M. A., Butcher E. C. Distinct roles of L-selectin and integrins alpha 4 beta 7 and LFA-1 in lymphocyte homing to Peyer's patch-HEV in situ: the multistep model confirmed and refined. Immunity. 1995 Jul;3(1):99–108. doi: 10.1016/1074-7613(95)90162-0. [DOI] [PubMed] [Google Scholar]
  5. Baumheter S., Singer M. S., Henzel W., Hemmerich S., Renz M., Rosen S. D., Lasky L. A. Binding of L-selectin to the vascular sialomucin CD34. Science. 1993 Oct 15;262(5132):436–438. doi: 10.1126/science.7692600. [DOI] [PubMed] [Google Scholar]
  6. Berg E. L., McEvoy L. M., Berlin C., Bargatze R. F., Butcher E. C. L-selectin-mediated lymphocyte rolling on MAdCAM-1. Nature. 1993 Dec 16;366(6456):695–698. doi: 10.1038/366695a0. [DOI] [PubMed] [Google Scholar]
  7. Berg E. L., Robinson M. K., Warnock R. A., Butcher E. C. The human peripheral lymph node vascular addressin is a ligand for LECAM-1, the peripheral lymph node homing receptor. J Cell Biol. 1991 Jul;114(2):343–349. doi: 10.1083/jcb.114.2.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Berlin C., Bargatze R. F., Campbell J. J., von Andrian U. H., Szabo M. C., Hasslen S. R., Nelson R. D., Berg E. L., Erlandsen S. L., Butcher E. C. alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995 Feb 10;80(3):413–422. doi: 10.1016/0092-8674(95)90491-3. [DOI] [PubMed] [Google Scholar]
  9. Berlin C., Berg E. L., Briskin M. J., Andrew D. P., Kilshaw P. J., Holzmann B., Weissman I. L., Hamann A., Butcher E. C. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993 Jul 16;74(1):185–195. doi: 10.1016/0092-8674(93)90305-a. [DOI] [PubMed] [Google Scholar]
  10. Briskin M. J., McEvoy L. M., Butcher E. C. MAdCAM-1 has homology to immunoglobulin and mucin-like adhesion receptors and to IgA1. Nature. 1993 Jun 3;363(6428):461–464. doi: 10.1038/363461a0. [DOI] [PubMed] [Google Scholar]
  11. Butcher E. C. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991 Dec 20;67(6):1033–1036. doi: 10.1016/0092-8674(91)90279-8. [DOI] [PubMed] [Google Scholar]
  12. Butcher E. C., Scollay R. G., Weissman I. L. Lymphocyte adherence to high endothelial venules: characterization of a modified in vitro assay, and examination of the binding of syngeneic and allogeneic lymphocyte populations. J Immunol. 1979 Nov;123(5):1996–2003. [PubMed] [Google Scholar]
  13. Chan B. M., Elices M. J., Murphy E., Hemler M. E. Adhesion to vascular cell adhesion molecule 1 and fibronectin. Comparison of alpha 4 beta 1 (VLA-4) and alpha 4 beta 7 on the human B cell line JY. J Biol Chem. 1992 Apr 25;267(12):8366–8370. [PubMed] [Google Scholar]
  14. Chien Y. H., Iwashima M., Wettstein D. A., Kaplan K. B., Elliott J. F., Born W., Davis M. M. T-cell receptor delta gene rearrangements in early thymocytes. Nature. 1987 Dec 24;330(6150):722–727. doi: 10.1038/330722a0. [DOI] [PubMed] [Google Scholar]
  15. De Togni P., Goellner J., Ruddle N. H., Streeter P. R., Fick A., Mariathasan S., Smith S. C., Carlson R., Shornick L. P., Strauss-Schoenberger J. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994 Apr 29;264(5159):703–707. doi: 10.1126/science.8171322. [DOI] [PubMed] [Google Scholar]
  16. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  17. Elliott J. F., Rock E. P., Patten P. A., Davis M. M., Chien Y. H. The adult T-cell receptor delta-chain is diverse and distinct from that of fetal thymocytes. Nature. 1988 Feb 18;331(6157):627–631. doi: 10.1038/331627a0. [DOI] [PubMed] [Google Scholar]
  18. Enver T., Raich N., Ebens A. J., Papayannopoulou T., Costantini F., Stamatoyannopoulos G. Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice. Nature. 1990 Mar 22;344(6264):309–313. doi: 10.1038/344309a0. [DOI] [PubMed] [Google Scholar]
  19. Friedberg S. H., Weissman I. L. Lymphoid tissue architecture. II. Ontogeny of peripheral T and B cells in mice: evidence against Peyer's patches as the site of generation of B cells. J Immunol. 1974 Nov;113(5):1477–1492. [PubMed] [Google Scholar]
  20. GOWANS J. L., KNIGHT E. J. THE ROUTE OF RE-CIRCULATION OF LYMPHOCYTES IN THE RAT. Proc R Soc Lond B Biol Sci. 1964 Jan 14;159:257–282. doi: 10.1098/rspb.1964.0001. [DOI] [PubMed] [Google Scholar]
  21. Gallatin W. M., Weissman I. L., Butcher E. C. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature. 1983 Jul 7;304(5921):30–34. doi: 10.1038/304030a0. [DOI] [PubMed] [Google Scholar]
  22. Garman R. D., Doherty P. J., Raulet D. H. Diversity, rearrangement, and expression of murine T cell gamma genes. Cell. 1986 Jun 6;45(5):733–742. doi: 10.1016/0092-8674(86)90787-7. [DOI] [PubMed] [Google Scholar]
  23. Gutman G. A., Weissman I. L. Homing properties of thymus-independent follicular lymphocytes. Transplantation. 1973 Dec;16(6):621–629. doi: 10.1097/00007890-197312000-00014. [DOI] [PubMed] [Google Scholar]
  24. Hakomori S. Blood group ABH and Ii antigens of human erythrocytes: chemistry, polymorphism, and their developmental change. Semin Hematol. 1981 Jan;18(1):39–62. [PubMed] [Google Scholar]
  25. Hamann A., Andrew D. P., Jablonski-Westrich D., Holzmann B., Butcher E. C. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol. 1994 Apr 1;152(7):3282–3293. [PubMed] [Google Scholar]
  26. Hardy R. R., Hayakawa K. A developmental switch in B lymphopoiesis. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11550–11554. doi: 10.1073/pnas.88.24.11550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hemmerich S., Butcher E. C., Rosen S. D. Sulfation-dependent recognition of high endothelial venules (HEV)-ligands by L-selectin and MECA 79, and adhesion-blocking monoclonal antibody. J Exp Med. 1994 Dec 1;180(6):2219–2226. doi: 10.1084/jem.180.6.2219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Holzmann B., McIntyre B. W., Weissman I. L. Identification of a murine Peyer's patch--specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha. Cell. 1989 Jan 13;56(1):37–46. doi: 10.1016/0092-8674(89)90981-1. [DOI] [PubMed] [Google Scholar]
  29. Holzmann B., Weissman I. L. Peyer's patch-specific lymphocyte homing receptors consist of a VLA-4-like alpha chain associated with either of two integrin beta chains, one of which is novel. EMBO J. 1989 Jun;8(6):1735–1741. doi: 10.1002/j.1460-2075.1989.tb03566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Howard J. C., Hunt S. V., Gowans J. L. Identification of marrow-derived and thymus-derived small lymphocytes in the lymphoid tissue and thoracic duct lymph of normal rats. J Exp Med. 1972 Feb 1;135(2):200–219. doi: 10.1084/jem.135.2.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hu M. C., Crowe D. T., Weissman I. L., Holzmann B. Cloning and expression of mouse integrin beta p(beta 7): a functional role in Peyer's patch-specific lymphocyte homing. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8254–8258. doi: 10.1073/pnas.89.17.8254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ikuta K., Kina T., MacNeil I., Uchida N., Peault B., Chien Y. H., Weissman I. L. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell. 1990 Sep 7;62(5):863–874. doi: 10.1016/0092-8674(90)90262-d. [DOI] [PubMed] [Google Scholar]
  33. Issekutz T. B. Inhibition of in vivo lymphocyte migration to inflammation and homing to lymphoid tissues by the TA-2 monoclonal antibody. A likely role for VLA-4 in vivo. J Immunol. 1991 Dec 15;147(12):4178–4184. [PubMed] [Google Scholar]
  34. Itohara S., Nakanishi N., Kanagawa O., Kubo R., Tonegawa S. Monoclonal antibodies specific to native murine T-cell receptor gamma delta: analysis of gamma delta T cells during thymic ontogeny and in peripheral lymphoid organs. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5094–5098. doi: 10.1073/pnas.86.13.5094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kelly K. A., Scollay R. Seeding of neonatal lymph nodes by T cells and identification of a novel population of CD3-CD4+ cells. Eur J Immunol. 1992 Feb;22(2):329–334. doi: 10.1002/eji.1830220207. [DOI] [PubMed] [Google Scholar]
  36. Kilshaw P. J., Baker K. C. A unique surface antigen on intraepithelial lymphocytes in the mouse. Immunol Lett. 1988 Jun;18(2):149–154. doi: 10.1016/0165-2478(88)90056-9. [DOI] [PubMed] [Google Scholar]
  37. Kilshaw P. J., Murant S. J. Expression and regulation of beta 7(beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur J Immunol. 1991 Oct;21(10):2591–2597. doi: 10.1002/eji.1830211041. [DOI] [PubMed] [Google Scholar]
  38. Lasky L. A., Singer M. S., Dowbenko D., Imai Y., Henzel W. J., Grimley C., Fennie C., Gillett N., Watson S. R., Rosen S. D. An endothelial ligand for L-selectin is a novel mucin-like molecule. Cell. 1992 Jun 12;69(6):927–938. doi: 10.1016/0092-8674(92)90612-g. [DOI] [PubMed] [Google Scholar]
  39. Lasky L. A., Singer M. S., Yednock T. A., Dowbenko D., Fennie C., Rodriguez H., Nguyen T., Stachel S., Rosen S. D. Cloning of a lymphocyte homing receptor reveals a lectin domain. Cell. 1989 Mar 24;56(6):1045–1055. doi: 10.1016/0092-8674(89)90637-5. [DOI] [PubMed] [Google Scholar]
  40. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  41. Mebius R. E., Brevé J., Kraal G., Streeter P. R. Developmental regulation of vascular addressin expression: a possible role for site-associated environments. Int Immunol. 1993 May;5(5):443–449. doi: 10.1093/intimm/5.5.443. [DOI] [PubMed] [Google Scholar]
  42. Miyake K., Weissman I. L., Greenberger J. S., Kincade P. W. Evidence for a role of the integrin VLA-4 in lympho-hemopoiesis. J Exp Med. 1991 Mar 1;173(3):599–607. doi: 10.1084/jem.173.3.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Papayannopoulou T., Nakamoto B., Agostinelli F., Manna M., Lucarelli G., Stamatoyannopoulos G. Fetal to adult hemopoietic cell transplantation in humans: insights into hemoglobin switching. Blood. 1986 Jan;67(1):99–104. [PubMed] [Google Scholar]
  44. Picker L. J., Butcher E. C. Physiological and molecular mechanisms of lymphocyte homing. Annu Rev Immunol. 1992;10:561–591. doi: 10.1146/annurev.iy.10.040192.003021. [DOI] [PubMed] [Google Scholar]
  45. Rüegg C., Postigo A. A., Sikorski E. E., Butcher E. C., Pytela R., Erle D. J. Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol. 1992 Apr;117(1):179–189. doi: 10.1083/jcb.117.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Scollay R. G., Butcher E. C., Weissman I. L. Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol. 1980 Mar;10(3):210–218. doi: 10.1002/eji.1830100310. [DOI] [PubMed] [Google Scholar]
  47. Shimizu Y., Newman W., Tanaka Y., Shaw S. Lymphocyte interactions with endothelial cells. Immunol Today. 1992 Mar;13(3):106–112. doi: 10.1016/0167-5699(92)90151-V. [DOI] [PubMed] [Google Scholar]
  48. Siegelman M. H., van de Rijn M., Weissman I. L. Mouse lymph node homing receptor cDNA clone encodes a glycoprotein revealing tandem interaction domains. Science. 1989 Mar 3;243(4895):1165–1172. doi: 10.1126/science.2646713. [DOI] [PubMed] [Google Scholar]
  49. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  50. Stamper H. B., Jr, Woodruff J. J. Lymphocyte homing into lymph nodes: in vitro demonstration of the selective affinity of recirculating lymphocytes for high-endothelial venules. J Exp Med. 1976 Sep 1;144(3):828–833. doi: 10.1084/jem.144.3.828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Streeter P. R., Berg E. L., Rouse B. T., Bargatze R. F., Butcher E. C. A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature. 1988 Jan 7;331(6151):41–46. doi: 10.1038/331041a0. [DOI] [PubMed] [Google Scholar]
  52. Streeter P. R., Rouse B. T., Butcher E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol. 1988 Nov;107(5):1853–1862. doi: 10.1083/jcb.107.5.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wood W. G., Bunch C., Kelly S., Gunn Y., Breckon G. Control of haemoglobin switching by a developmental clock? Nature. 1985 Jan 24;313(6000):320–323. doi: 10.1038/313320a0. [DOI] [PubMed] [Google Scholar]
  54. Zanjani E. D., Lim G., McGlave P. B., Clapp J. F., Mann L. I., Norwood T. H., Stamatoyannopoulos G. Adult haematopoietic cells transplanted to sheep fetuses continue to produce adult globins. Nature. 1982 Jan 21;295(5846):244–246. doi: 10.1038/295244a0. [DOI] [PubMed] [Google Scholar]

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