CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism
| Autor: | Giulia Casorati, Paolo Dellabona, Alessandra Rovida, Matteo Bellone, Jessica Bordini, Matteo Grioni, Arianna Brevi, Maria Teresa Sabrina Bertilaccio, Arianna Calcinotto, Elena Cattaneo, Maurilio Ponzoni, Paolo Ghia |
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| Přispěvatelé: | Grioni, M., Brevi, A., Cattaneo, E., Rovida, A., Bordini, J., Bertilaccio, M. T. S., Ponzoni, M., Casorati, G., Dellabona, P., Ghia, P., Bellone, M., Calcinotto, A. |
| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Adoptive cell transfer Immunobiology and Immunotherapy medicine.drug_class Chronic lymphocytic leukemia CD40 Ligand Mice Transgenic Monoclonal antibody Flow cytometry Mice 03 medical and health sciences 0302 clinical medicine immune system diseases Proto-Oncogene Proteins hemic and lymphatic diseases medicine Animals CD40 Dromaiidae biology medicine.diagnostic_test Chemistry Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Antibody CD5 CD8 |
| Zdroj: | Blood Adv |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eμ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40−/−), or CD8+ T cells (TCL1+/+TAP−/−), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP−/− mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L−/− mice, and TCL1+/+CD40−/− mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms. |
| Databáze: | OpenAIRE |
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