L’importance de la coopération de TRAF1 et LSP1 en aval du récepteur  4-1BB(CD137) pour la survie des lymphocytes

4-1BB (CD137) is a member of the TNFR superfamily, which is involved in the transmission of survival signals in lymphocytes. TRAF1 is an adapter protein that is recruited by 4-1BB and other TNFRs and is characterized by a very restricted expression in lymphocytes, dendritic cells and some epithelial cells. TRAF1 is necessary for the expansion and survival of memory T cells in the presence of anti-4-1BB agonist in vivo. Also, TRAF1 is required downstream of 4-1BB to activate (phosphorylate) the MAP kinase ERK involved in the regulation of the proapoptotic molecule Bim. Upon activation of 4-1BB, TRAF1 and ERK are involved in the phosphorylation of Bim and modulation of its expression. The activation and regulation of TRAF1 and Bim have an important role in the survival of CD8 memory T cells. In this study, we used a proteomic approach in order to identify new TRAF1 binding partners. Using this strategy, we have identified that LSP1 (Leukocyte Specific Protein 1) is recruited to the 4-1BB signaling complex in a TRAF1-dependent manner. It has been shown that LSP1 is a target protein for signaling ERK / MAP kinase. Further characterization of the interaction between TRAF1 and LSP1 has shown that LSP1 binds the N-terminal unique region independently of the conserved C-terminal of TRAF1. Like the T cells deficient in TRAF1, T cells deficient in LSP1 are not capable of activating ERK downstream of 4-1BB and therefore cannot regulate Bim levels in T cells. Thus, TRAF1 and LSP1 cooperate downstream of 4-1BB in order to activate ERK and regulate Bim levels in murine CD8 T cells. According to the literature, the 4-1BB receptor is not expressed on the surface of murine CD19+ B cells, but 4-1BB activation promotes the proliferation and survival of human CD19+B cells. However, it is important to study the expression of 4-1BB receptor in murine B cells to have a murine model and predict the clinical response to the manipulation of 4-1BB. Using different stimulation of primary murine CD19+B cells, we have found that the 4-1BB receptor is expressed on the surface of murine B cells in response to LPS (lipopolysaccharide) stimulation. Further characterization showed that the 4-1BB was induced in murine CD19+B cells in a TLR4-dependent manner (Toll like Receptor 4). Collectively, our work has shown that the stimulation with LPS induces the expression of 4-1BB on the surface of murine B cells leading to the induction of TRAF1. Also, TRAF1 and LSP1 cooperate downstream of 4-1BB to activate the signaling of the Map kinase ERK in murine B cells similarly to T cells. Similarly, as for the T cells, TRAF1-/- B cells or LSP1-/- B cells are not able to activate the ERK pathway downstream of 4-1BB. In addition, the B cells deficient in either TRAF1 or LSP1 show a level of expression of the 4-1BB receptor significantly decreased compared to B cells from a WT mouse. Thus, TRAF1 and LSP1 are required for maximal expression of the 4-1BB receptor on the cell surface of murine B cells and cooperate downstream of 4-1BB to activate the ERK cascade in the murine B cells.

Keyphrases: 4-1BB(CD137), lymphocytes T et B, TRAF1, LSP1, co-stimulation, survival of healthy and malignant cells, lymphocytes T and B, co-stimulation, leukemia