The interaction of the CD40-receptor expressed on B-lymphocytes with its ligand CD40L (gp39) on T-lymphocytes has been shown to be crucial for the activation of B-lymphocytes. Stimulation via the CD40 molecule induces cell proliferation, generation of memory B cells and Ig isotype switching and prevents apoptosis of B-lymphocytes in germinal centers of lymph nodes.

Small deletions or point mutations within the gene coding for the CD40 ligand (CD40L) result in the X-linked hyper-IgM syndrome, a disease characterized by high levels of IgM, inefficient synthesis of IgG, IgE or IgA, recurrent bacterial and pneumocystis carinii infections and an increased risk for autoimmune diseases and malignancies.

Recently, we have demonstrated an activation of the Ras pathway via tyrosine kinases and diglycerides in B-lymphocytes upon CD40-receptor triggering.

Here, we show, that the CD40L also functions as a signaling molecule in T-lymphocytes. Stimulation of Jurkat, EL-4 or peripheral blood lymphocytes via the CD40L results in the activation of the src-family kinase p56lck, a tyrosine phosphorylation of several cellular proteins including the gp39 protein itself, an association of p56lck and CD40L, an activation of Rac proteins, a stimulation of JNK/p38-kinases and a synthesis of Interleukin 2(IL-2). Inhibition of src-kinases by the specific tyrosine kinase inhibitor Herbimycin A prevents all observed signaling events pointing to a signaling cascade from the CD40L via src-kinases to JNK and transcription factors regulating the synthesis of IL2. Further, we detected a stimulation of Ca2+ and IP3 release as well as an activation of PKC. These data suggest that the CD40L functions not only as a ligand for the CD40 molecule. Rather, gp39 seems to have also a signaling function resulting in T-cell activation upon ligation of gp39.

Funded by DFG grant (315/6-1).