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

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 CD41 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 CD41 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 CD81 T cells restrain CLL progression, whereas CD41 T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.