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.