Background: Like innate cells, B cells also express Pattern Recognition Receptors (PRRs) to detect danger signal such as tissue damage or pathogen intrusion. Production of specific antibodies by plasma cells results from the activation and differentiation of B cells following three signals: (i) antigen recognition by B Cell Receptors, (ii) recognition of danger and (iii) T-cell help. However, it is unclear whether T-cell help is dispensable for B cell activation and differentiation or not. Few studies have investigated the role of cytosolic PRRs such as NOD1 in B cell differentiation. Methods: We used splenic C57BL6J B cells to evaluate NOD1 expression and then assessed the effect of stimulation with C12-iE-DAP, a NOD1 ligand, with or without CD40L as a T-cell help signal on B-cell responses globally or according to their CD23 expression level. Results: We showed that murine B cells express NOD1 and that the presence of C12-iE-DAP induces activation, proliferation and initiates differentiation in plasma cells even in the absence of a T-dependent signal. Surprisingly, CD23high B cells are more sensitive than CD23low B cells to stimulation. Conclusion: Our results suggest that the NLR pathway could induce antibody development during infections and be exploited to develop more effective vaccinationn.