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The depletion of differential B cell and xenoreactive natural antibodies (XNA) by anti-δ and anti-μ injections was analyzed in adult mice. Sequential treatment with anti-δ and then anti-μ induces a complete depletion of B cells and XNA and represents a potential approach to induce xenograft tolerance.Adult mice were injected with anti-μ, anti-δ, anti-δ then anti-μ, or control isotype monoclonal antibodies from day 0 to day 14. The different B-cell populations were analyzed by FACS and immunohistology. Ig production was tested by ELISA. XNA were analyzed by FACS.Anti-μ injections induced a depletion of IgMhigh, immature B cells, marginal zone B cells, and B1 cells and an increase of IgG-XNA production. Anti-δ injections induced mature conventional IgDhigh B-cell depletion and increased IgM-XNA production. Interestingly, sequential injections of anti-δ then anti-μ induced a depletion of immature B cells, mature B cells (MZ, B2, and B1), and XNA.These results demonstrate that mature B-cell depletion in adult mice can be obtained by mAb injections and depends on the surface immunoglobulin cross-linking threshold. Indeed, anti-μ mAb depleted IgMhigh B cells (MZ and B1) and anti-δ, IgDhigh B cells (B2). The differential B-cell suppression shows that conventional B cells are responsible in the IgG-XNA production and MZ and B1 cells in the IgM-XNA production. Sequential repeated injections of anti-δ then anti-μ mAb depleted all B-cell populations and suppressed the whole XNA production.