Abstract
Although CD40 has been extensively studied in B- and T-cell non-Hodgkin's lymphomas (NHLs)/leukemias, and more recently in Hodgkin's disease (HD), little is known about the expression of its ligand (CD40L) in lymphoproliferative disorders other than T-cell NHLs/leukemias. A series of 121 lymphoma/leukemia samples, including 35 cases of HD, 34 T-cell and 39 B-cells NHLs, 2 cases of adult T-cell leukemia/lymphoma, and 11 cases of T-cell acute lymphoblastic leukemia, were evaluated for CD40L expression by immunostaining of frozen tissue sections and flow cytometry with the anti-CD40L monoclonal antibody M90. CD40L was constitutively expressed by neoplastic cells in 15 of 36 (42%) T-cell NHLs/adult T-cell leukemia/lymphomas, almost invariably those displaying the CD4+/CD8- phenotype, whereas no CD40L-expressing tumor cells could be found in B-cell NHL and HD. Among T-cell acute lymphoblastic leukemias, CD40L was detected only on 2 cases displaying a stem-cell-like phenotype. In follicular B-cell lymphomas a large number of CD40L-expressing CD3+/CD4+ T lymphocytes were found admixed with tumor cells within the neoplastic follicles and in their surrounding areas. In the nonfollicular B-cell lymphomas, CD40L-positive CD3+/CD4+ T lymphocytes were few or absent. In all HD subtypes other than the nodular lymphocytic predominance, CD40L-expressing CD3+/CD4+ T lymphocytes were numerous in the HD-involved areas and were mainly located in close proximity to the Reed-Sternberg cells. Our data indicate that in human lymphomas CD40L is preferentially expressed by a restricted subset of T-cell lymphomas, mostly with CD4 immunophenotype. Finally, we have provided morphological evidence that CD40L may play an important role in the cell contact-dependent interaction of tumor B-cells (CD40+) within the neoplastic follicles or Reed-Sternberg cells (CD40+) in HD-involved areas and the microenvironmental CD3+/CD4+/CD40L+ T lymphocytes.
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- Armitage R. J., Macduff B. M., Spriggs M. K., Fanslow W. C. Human B cell proliferation and Ig secretion induced by recombinant CD40 ligand are modulated by soluble cytokines. J Immunol. 1993 May 1;150(9):3671–3680. [PubMed] [Google Scholar]
- Armitage R. J., Tough T. W., Macduff B. M., Fanslow W. C., Spriggs M. K., Ramsdell F., Alderson M. R. CD40 ligand is a T cell growth factor. Eur J Immunol. 1993 Sep;23(9):2326–2331. doi: 10.1002/eji.1830230941. [DOI] [PubMed] [Google Scholar]
- Banchereau J., Bazan F., Blanchard D., Brière F., Galizzi J. P., van Kooten C., Liu Y. J., Rousset F., Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881–922. doi: 10.1146/annurev.iy.12.040194.004313. [DOI] [PubMed] [Google Scholar]
- Carbone A., Gloghini A., Gattei V., Aldinucci D., Degan M., De Paoli P., Zagonel V., Pinto A. Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin's disease cell lines. Blood. 1995 Feb 1;85(3):780–789. [PubMed] [Google Scholar]
- Carbone A., Gloghini A., Volpe R. Immunohistochemistry of Hodgkin and non-Hodgkin lymphomas with emphasis on the diagnostic significance of the BNH9 antibody reactivity with anaplastic large cell (CD30 positive) lymphomas. Cancer. 1992 Dec 1;70(11):2691–2698. doi: 10.1002/1097-0142(19921201)70:11<2691::aid-cncr2820701121>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
- Carbone A., Gloghini A., Volpe R. Paraffin section immunohistochemistry in the diagnosis of Hodgkin's disease and anaplastic large cell (CD30+) lymphomas. Virchows Arch A Pathol Anat Histopathol. 1992;420(6):527–532. doi: 10.1007/BF01600258. [DOI] [PubMed] [Google Scholar]
- Caux C., Massacrier C., Vanbervliet B., Dubois B., Van Kooten C., Durand I., Banchereau J. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994 Oct 1;180(4):1263–1272. doi: 10.1084/jem.180.4.1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cayabyab M., Phillips J. H., Lanier L. L. CD40 preferentially costimulates activation of CD4+ T lymphocytes. J Immunol. 1994 Feb 15;152(4):1523–1531. [PubMed] [Google Scholar]
- Clark E. A., Ledbetter J. A. How B and T cells talk to each other. Nature. 1994 Feb 3;367(6462):425–428. doi: 10.1038/367425a0. [DOI] [PubMed] [Google Scholar]
- Cordell J. L., Falini B., Erber W. N., Ghosh A. K., Abdulaziz Z., MacDonald S., Pulford K. A., Stein H., Mason D. Y. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. doi: 10.1177/32.2.6198355. [DOI] [PubMed] [Google Scholar]
- Ferrara F., Cimino R., Antinolfi I., De Rosa C., Mele G., Mettivier V., Fusco C., Del Vecchio L. Clinical relevance of immunological dissection in T-ALL: a report on 20 cases with stem cell (CD7+, CD4-, CD8-, CD1-) phenotype. Am J Hematol. 1992 Jun;40(2):98–102. doi: 10.1002/ajh.2830400205. [DOI] [PubMed] [Google Scholar]
- Ford R. J., Tamayo A., Li D. J., Cabanillas F. Human B cell lymphomas: in vitro and in vivo studies on growth factors and cell growth. Leuk Lymphoma. 1993;10 (Suppl):51–56. doi: 10.3109/10428199309149112. [DOI] [PubMed] [Google Scholar]
- Gloghini A., Carbone A. The nonlymphoid microenvironment of reactive follicles and lymphomas of follicular origin as defined by immunohistology on paraffin-embedded tissues. Hum Pathol. 1993 Jan;24(1):67–76. doi: 10.1016/0046-8177(93)90065-o. [DOI] [PubMed] [Google Scholar]
- Gruss H. J., Hirschstein D., Wright B., Ulrich D., Caligiuri M. A., Barcos M., Strockbine L., Armitage R. J., Dower S. K. Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease. Blood. 1994 Oct 1;84(7):2305–2314. [PubMed] [Google Scholar]
- Hollenbaugh D., Grosmaire L. S., Kullas C. D., Chalupny N. J., Braesch-Andersen S., Noelle R. J., Stamenkovic I., Ledbetter J. A., Aruffo A. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992 Dec;11(12):4313–4321. doi: 10.1002/j.1460-2075.1992.tb05530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsu S. M., Raine L., Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol. 1981 May;75(5):734–738. doi: 10.1093/ajcp/75.5.734. [DOI] [PubMed] [Google Scholar]
- Hsu S. M., Waldron J. W., Jr, Hsu P. L., Hough A. J., Jr Cytokines in malignant lymphomas: review and prospective evaluation. Hum Pathol. 1993 Oct;24(10):1040–1057. doi: 10.1016/0046-8177(93)90183-h. [DOI] [PubMed] [Google Scholar]
- Inghirami G., Lederman S., Yellin M. J., Chadburn A., Chess L., Knowles D. M. Phenotypic and functional characterization of T-BAM (CD40 ligand)+ T-cell non-Hodgkin's lymphoma. Blood. 1994 Aug 1;84(3):866–872. [PubMed] [Google Scholar]
- Johnson P. W., Watt S. M., Betts D. R., Davies D., Jordan S., Norton A. J., Lister T. A. Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. Blood. 1993 Sep 15;82(6):1848–1857. [PubMed] [Google Scholar]
- Kadin M. E. Pathology of Hodgkin's disease. Curr Opin Oncol. 1994 Sep;6(5):456–463. doi: 10.1097/00001622-199409000-00002. [DOI] [PubMed] [Google Scholar]
- Kurtzberg J., Waldmann T. A., Davey M. P., Bigner S. H., Moore J. O., Hershfield M. S., Haynes B. F. CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells. Blood. 1989 Feb;73(2):381–390. [PubMed] [Google Scholar]
- Lane P., Traunecker A., Hubele S., Inui S., Lanzavecchia A., Gray D. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. Eur J Immunol. 1992 Oct;22(10):2573–2578. doi: 10.1002/eji.1830221016. [DOI] [PubMed] [Google Scholar]
- Law C. L., Wörmann B., LeBien T. W. Analysis of expression and function of CD40 on normal and leukemic human B cell precursors. Leukemia. 1990 Nov;4(11):732–738. [PubMed] [Google Scholar]
- Lederman S., Yellin M. J., Inghirami G., Lee J. J., Knowles D. M., Chess L. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. J Immunol. 1992 Dec 15;149(12):3817–3826. [PubMed] [Google Scholar]
- Lederman S., Yellin M. J., Krichevsky A., Belko J., Lee J. J., Chess L. Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help). J Exp Med. 1992 Apr 1;175(4):1091–1101. doi: 10.1084/jem.175.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu Y. J., Mason D. Y., Johnson G. D., Abbot S., Gregory C. D., Hardie D. L., Gordon J., MacLennan I. C. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol. 1991 Aug;21(8):1905–1910. doi: 10.1002/eji.1830210819. [DOI] [PubMed] [Google Scholar]
- Nishioka Y., Lipsky P. E. The role of CD40-CD40 ligand interaction in human T cell-B cell collaboration. J Immunol. 1994 Aug 1;153(3):1027–1036. [PubMed] [Google Scholar]
- Pinto A., Gloghini A., Gattei V., Aldinucci D., Zagonel V., Carbone A. Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas. Blood. 1994 Feb 1;83(3):785–792. [PubMed] [Google Scholar]
- Poppema S. The nature of the lymphocytes surrounding Reed-Sternberg cells in nodular lymphocyte predominance and in other types of Hodgkin's disease. Am J Pathol. 1989 Aug;135(2):351–357. [PMC free article] [PubMed] [Google Scholar]
- Saeland S., Duvert V., Caux C., Pandrau D., Favre C., Vallé A., Durand I., Charbord P., de Vries J., Banchereau J. Distribution of surface-membrane molecules on bone marrow and cord blood CD34+ hematopoietic cells. Exp Hematol. 1992 Jan;20(1):24–33. [PubMed] [Google Scholar]
- Schriever F., Freedman A. S., Freeman G., Messner E., Lee G., Daley J., Nadler L. M. Isolated human follicular dendritic cells display a unique antigenic phenotype. J Exp Med. 1989 Jun 1;169(6):2043–2058. doi: 10.1084/jem.169.6.2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
- Spriggs M. K., Armitage R. J., Strockbine L., Clifford K. N., Macduff B. M., Sato T. A., Maliszewski C. R., Fanslow W. C. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992 Dec 1;176(6):1543–1550. doi: 10.1084/jem.176.6.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stamenkovic I., Clark E. A., Seed B. A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J. 1989 May;8(5):1403–1410. doi: 10.1002/j.1460-2075.1989.tb03521.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Uckun F. M., Gajl-Peczalska K., Myers D. E., Jaszcz W., Haissig S., Ledbetter J. A. Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells. Blood. 1990 Dec 15;76(12):2449–2456. [PubMed] [Google Scholar]
- Umetsu D. T., Esserman L., Donlon T. A., DeKruyff R. H., Levy R. Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones. J Immunol. 1990 Apr 1;144(7):2550–2557. [PubMed] [Google Scholar]
- Wagner D. H., Jr, Stout R. D., Suttles J. Role of the CD40-CD40 ligand interaction in CD4+ T cell contact-dependent activation of monocyte interleukin-1 synthesis. Eur J Immunol. 1994 Dec;24(12):3148–3154. doi: 10.1002/eji.1830241235. [DOI] [PubMed] [Google Scholar]
- Westendorf J. J., Ahmann G. J., Armitage R. J., Spriggs M. K., Lust J. A., Greipp P. R., Katzmann J. A., Jelinek D. F. CD40 expression in malignant plasma cells. Role in stimulation of autocrine IL-6 secretion by a human myeloma cell line. J Immunol. 1994 Jan 1;152(1):117–128. [PubMed] [Google Scholar]
- van Kooten C., Gaillard C., Galizzi J. P., Hermann P., Fossiez F., Banchereau J., Blanchard D. B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40. Eur J Immunol. 1994 Apr;24(4):787–792. doi: 10.1002/eji.1830240402. [DOI] [PubMed] [Google Scholar]