CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

Author:

Grioni Matteo1,Brevi Arianna1,Cattaneo Elena1,Rovida Alessandra2,Bordini Jessica2,Bertilaccio Maria Teresa Sabrina3ORCID,Ponzoni Maurilio34,Casorati Giulia5,Dellabona Paolo5ORCID,Ghia Paolo24,Bellone Matteo1ORCID,Calcinotto Arianna1ORCID

Affiliation:

1. Cellular Immunology Unit, Division of Immunology, Transplantation, and Infectious Diseases,

2. Unit of B Cell Neoplasia, Division of Experimental Oncology, and

3. Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy;

4. Università Vita-Salute San Raffaele, Milan, Italy; and

5. Experimental Immunology Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Hematology

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