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. 1994 Nov 1;180(5):1849–1860. doi: 10.1084/jem.180.5.1849

The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro

PMCID: PMC2191729  PMID: 7525841

Abstract

B7-2 is a recently discovered, second ligand for the CTLA-4/CD28, T cell signaling system. Using the GL-1 rat monoclonal antibody (mAb), we monitored expression of B7-2 on mouse leukocytes with an emphasis on dendritic cells. By cytofluorography, little or no B7-2 was detected on most cell types isolated from spleen, thymus, peritoneal cavity, skin, marrow, and blood. However, expression of B7-2 could be upregulated in culture. In the case of epidermal and spleen dendritic cells, which become highly immunostimulatory for T cells during a short period of culture, the upregulation of B7-2 was dramatic and did not require added stimuli. Lipopolysaccharide did not upregulate B7-2 levels on dendritic cells, in contrast to macrophages and B cells. By indirect immunolabeling, the level of staining with GL-1 mAb exceeded that seen with rat mAbs to several other surface molecules including intercellular adhesion molecule 1, B7-1, CD44, and CD45, as well as new hamster mAbs to CD40, CD48, and B7-1/CD80. Of these accessory molecules, B7-2 was a major species that increased in culture, implying a key role for B7-2 in the functional maturation of dendritic cells. B7- 2 was the main (> 90%) CTLA-4 ligand on mouse dendritic cells. When we applied GL-1 to tissue sections of a dozen different organs, clear-cut staining with B7-2 antigen was found in many. B7-2 staining was noted on liver Kupffer cells, interstitial cells of heart and lung, and profiles in the submucosa of the esophagus. B7-2 staining was minimal in the kidney and in the nonlymphoid regions of the gut, and was not observed at all in the brain. In the tongue, only rare dendritic cells in the oral epithelium were B7-2+, but reactive cells were scattered about the interstitial spaces of the muscle. In all lymphoid tissues, Gl-1 strongly stained certain distinct regions that are occupied by dendritic cells and by macrophages. For dendritic cells, these include the thymic medulla, splenic periarterial sheaths, and lymph node deep cortex; for macrophages, the B7-2-rich regions included the splenic marginal zone and lymph node subcapsular cortex. Splenic B7-2+ cells were accessible to labeling with GL-1 mAb given intravenously. Dendritic cell stimulation of T cells (DNA synthesis) during the mixed leukocyte reaction was significantly (35-65%) blocked by GL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Agger R., Witmer-Pack M., Romani N., Stossel H., Swiggard W. J., Metlay J. P., Storozynsky E., Freimuth P., Steinman R. M. Two populations of splenic dendritic cells detected with M342, a new monoclonal to an intracellular antigen of interdigitating dendritic cells and some B lymphocytes. J Leukoc Biol. 1992 Jul;52(1):34–42. doi: 10.1002/jlb.52.1.34. [DOI] [PubMed] [Google Scholar]
  2. Austyn J. M., Steinman R. M., Weinstein D. E., Granelli-Piperno A., Palladino M. A. Dendritic cells initiate a two-stage mechanism for T lymphocyte proliferation. J Exp Med. 1983 Apr 1;157(4):1101–1115. doi: 10.1084/jem.157.4.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Barclay A. N., Mayrhofer G. Bone marrow origin of Ia-positive cells in the medulla rat thymus. J Exp Med. 1981 Jun 1;153(6):1666–1671. doi: 10.1084/jem.153.6.1666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
  6. Crocker P. R., Gordon S. Mouse macrophage hemagglutinin (sheep erythrocyte receptor) with specificity for sialylated glycoconjugates characterized by a monoclonal antibody. J Exp Med. 1989 Apr 1;169(4):1333–1346. doi: 10.1084/jem.169.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Crowley M. T., Inaba K., Witmer-Pack M. D., Gezelter S., Steinman R. M. Use of the fluorescence activated cell sorter to enrich dendritic cells from mouse spleen. J Immunol Methods. 1990 Oct 4;133(1):55–66. doi: 10.1016/0022-1759(90)90318-p. [DOI] [PubMed] [Google Scholar]
  8. Dijkstra C. D. Characterization of nonlymphoid cells in rat spleen, with special reference to strongly Ia-positive branched cells in T-cell areas. J Reticuloendothel Soc. 1982 Sep;32(3):167–178. [PubMed] [Google Scholar]
  9. Duijvestijn A. M., Schutte R., Köhler Y. G., Korn C., Hoefsmit E. C. Characterization of the population of phagocytic cells in thymic cell suspensions. A morphological and cytochemical study. Cell Tissue Res. 1983;231(2):313–323. doi: 10.1007/BF00222183. [DOI] [PubMed] [Google Scholar]
  10. Fossum S. Lymph-borne dendritic leucocytes do not recirculate, but enter the lymph node paracortex to become interdigitating cells. Scand J Immunol. 1988 Jan;27(1):97–105. doi: 10.1111/j.1365-3083.1988.tb02326.x. [DOI] [PubMed] [Google Scholar]
  11. Fraser J. D., Irving B. A., Crabtree G. R., Weiss A. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science. 1991 Jan 18;251(4991):313–316. doi: 10.1126/science.1846244. [DOI] [PubMed] [Google Scholar]
  12. Freeman G. J., Borriello F., Hodes R. J., Reiser H., Gribben J. G., Ng J. W., Kim J., Goldberg J. M., Hathcock K., Laszlo G. Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J Exp Med. 1993 Dec 1;178(6):2185–2192. doi: 10.1084/jem.178.6.2185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freeman G. J., Borriello F., Hodes R. J., Reiser H., Hathcock K. S., Laszlo G., McKnight A. J., Kim J., Du L., Lombard D. B. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science. 1993 Nov 5;262(5135):907–909. doi: 10.1126/science.7694362. [DOI] [PubMed] [Google Scholar]
  14. Freeman G. J., Gray G. S., Gimmi C. D., Lombard D. B., Zhou L. J., White M., Fingeroth J. D., Gribben J. G., Nadler L. M. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med. 1991 Sep 1;174(3):625–631. doi: 10.1084/jem.174.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Gimmi C. D., Freeman G. J., Gribben J. G., Sugita K., Freedman A. S., Morimoto C., Nadler L. M. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6575–6579. doi: 10.1073/pnas.88.15.6575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hara T., Fu S. M., Hansen J. A. Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen). J Exp Med. 1985 Jun 1;161(6):1513–1524. doi: 10.1084/jem.161.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harding F. A., Allison J. P. CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help. J Exp Med. 1993 Jun 1;177(6):1791–1796. doi: 10.1084/jem.177.6.1791. [DOI] [PMC free article] [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. Harper K., Balzano C., Rouvier E., Mattéi M. G., Luciani M. F., Golstein P. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol. 1991 Aug 1;147(3):1037–1044. [PubMed] [Google Scholar]
  21. 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]
  22. Hathcock K. S., Laszlo G., Pucillo C., Linsley P., Hodes R. J. Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function. J Exp Med. 1994 Aug 1;180(2):631–640. doi: 10.1084/jem.180.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Heufler C., Koch F., Schuler G. Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med. 1988 Feb 1;167(2):700–705. doi: 10.1084/jem.167.2.700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Inaba K., Inaba M., Romani N., Aya H., Deguchi M., Ikehara S., Muramatsu S., Steinman R. M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992 Dec 1;176(6):1693–1702. doi: 10.1084/jem.176.6.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jenkinson E. J., Anderson G., Owen J. J. Studies on T cell maturation on defined thymic stromal cell populations in vitro. J Exp Med. 1992 Sep 1;176(3):845–853. doi: 10.1084/jem.176.3.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kato K., Koyanagi M., Okada H., Takanashi T., Wong Y. W., Williams A. F., Okumura K., Yagita H. CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation. J Exp Med. 1992 Nov 1;176(5):1241–1249. doi: 10.1084/jem.176.5.1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Klinkert W. E., LaBadie J. H., O'Brien J. P., Beyer C. F., Bowers W. E. Rat dendritic cells function as accessory cells and control the production of a soluble factor required for mitogenic responses of T lymphocytes. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5414–5418. doi: 10.1073/pnas.77.9.5414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Koide S. L., Inaba K., Steinman R. M. Interleukin 1 enhances T-dependent immune responses by amplifying the function of dendritic cells. J Exp Med. 1987 Feb 1;165(2):515–530. doi: 10.1084/jem.165.2.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Koulova L., Clark E. A., Shu G., Dupont B. The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells. J Exp Med. 1991 Mar 1;173(3):759–762. doi: 10.1084/jem.173.3.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kraal G., Breel M., Janse M., Bruin G. Langerhans' cells, veiled cells, and interdigitating cells in the mouse recognized by a monoclonal antibody. J Exp Med. 1986 Apr 1;163(4):981–997. doi: 10.1084/jem.163.4.981. [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. Lenz A., Heine M., Schuler G., Romani N. Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. J Clin Invest. 1993 Dec;92(6):2587–2596. doi: 10.1172/JCI116873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lesslauer W., Koning F., Ottenhoff T., Giphart M., Goulmy E., van Rood J. J. T90/44 (9.3 antigen). A cell surface molecule with a function in human T cell activation. Eur J Immunol. 1986 Oct;16(10):1289–1296. doi: 10.1002/eji.1830161017. [DOI] [PubMed] [Google Scholar]
  34. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. 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]
  37. 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]
  38. Linsley P. S., Greene J. L., Tan P., Bradshaw J., Ledbetter J. A., Anasetti C., Damle N. K. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med. 1992 Dec 1;176(6):1595–1604. doi: 10.1084/jem.176.6.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Martin P. J., Ledbetter J. A., Morishita Y., June C. H., Beatty P. G., Hansen J. A. A 44 kilodalton cell surface homodimer regulates interleukin 2 production by activated human T lymphocytes. J Immunol. 1986 May 1;136(9):3282–3287. [PubMed] [Google Scholar]
  40. Metlay J. P., Witmer-Pack M. D., Agger R., Crowley M. T., Lawless D., Steinman R. M. The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med. 1990 May 1;171(5):1753–1771. doi: 10.1084/jem.171.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nussenzweig M. C., Steinman R. M., Unkeless J. C., Witmer M. D., Gutchinov B., Cohn Z. A. Studies of the cell surface of mouse dendritic cells and other leukocytes. J Exp Med. 1981 Jul 1;154(1):168–187. doi: 10.1084/jem.154.1.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. O'Doherty U., Steinman R. M., Peng M., Cameron P. U., Gezelter S., Kopeloff I., Swiggard W. J., Pope M., Bhardwaj N. Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium. J Exp Med. 1993 Sep 1;178(3):1067–1076. doi: 10.1084/jem.178.3.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Powers G. D., Faherty D. A., Connaughton S. E., Biondi D. A., Godfrey D. I., Gault A., Chen C. Y., Nabavi N. Expression and functional analysis of murine B7 delineated by a novel monoclonal antibody. Cell Immunol. 1994 Feb;153(2):298–311. doi: 10.1006/cimm.1994.1030. [DOI] [PubMed] [Google Scholar]
  44. Rabinowitz S. S., Gordon S. Macrosialin, a macrophage-restricted membrane sialoprotein differentially glycosylated in response to inflammatory stimuli. J Exp Med. 1991 Oct 1;174(4):827–836. doi: 10.1084/jem.174.4.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Razi-Wolf Z., Freeman G. J., Galvin F., Benacerraf B., Nadler L., Reiser H. Expression and function of the murine B7 antigen, the major costimulatory molecule expressed by peritoneal exudate cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4210–4214. doi: 10.1073/pnas.89.9.4210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Reiser H., Freeman G. J., Razi-Wolf Z., Gimmi C. D., Benacerraf B., Nadler L. M. Murine B7 antigen provides an efficient costimulatory signal for activation of murine T lymphocytes via the T-cell receptor/CD3 complex. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):271–275. doi: 10.1073/pnas.89.1.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schuler G., Steinman R. M. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med. 1985 Mar 1;161(3):526–546. doi: 10.1084/jem.161.3.526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Seder R. A., Germain R. N., Linsley P. S., Paul W. E. CD28-mediated costimulation of interleukin 2 (IL-2) production plays a critical role in T cell priming for IL-4 and interferon gamma production. J Exp Med. 1994 Jan 1;179(1):299–304. doi: 10.1084/jem.179.1.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Spencer S. C., Fabre J. W. Characterization of the tissue macrophage and the interstitial dendritic cell as distinct leukocytes normally resident in the connective tissue of rat heart. J Exp Med. 1990 Jun 1;171(6):1841–1851. doi: 10.1084/jem.171.6.1841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Verweij C. L., Geerts M., Aarden L. A. Activation of interleukin-2 gene transcription via the T-cell surface molecule CD28 is mediated through an NF-kB-like response element. J Biol Chem. 1991 Aug 5;266(22):14179–14182. [PubMed] [Google Scholar]
  51. Witmer-Pack M. D., Crowley M. T., Inaba K., Steinman R. M. Macrophages, but not dendritic cells, accumulate colloidal carbon following administration in situ. J Cell Sci. 1993 Aug;105(Pt 4):965–973. doi: 10.1242/jcs.105.4.965. [DOI] [PubMed] [Google Scholar]
  52. Witmer-Pack M. D., Olivier W., Valinsky J., Schuler G., Steinman R. M. Granulocyte/macrophage colony-stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells. J Exp Med. 1987 Nov 1;166(5):1484–1498. doi: 10.1084/jem.166.5.1484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Witmer M. D., Steinman R. M. The anatomy of peripheral lymphoid organs with emphasis on accessory cells: light-microscopic immunocytochemical studies of mouse spleen, lymph node, and Peyer's patch. Am J Anat. 1984 Jul;170(3):465–481. doi: 10.1002/aja.1001700318. [DOI] [PubMed] [Google Scholar]
  54. Young J. W., Koulova L., Soergel S. A., Clark E. A., Steinman R. M., Dupont B. The B7/BB1 antigen provides one of several costimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro. J Clin Invest. 1992 Jul;90(1):229–237. doi: 10.1172/JCI115840. [DOI] [PMC free article] [PubMed] [Google Scholar]

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