Transplantation of human spleen into immunodeficient NOD/SCID IL2Rγnull mice generates humanized mice that improve functional B cell development

•Human thymus, bone, spleen and FL-CD34+ HSCs were transplanted into immunodeficient mice (TBS34N).•The spleen grafts in TBS34N mice were maintained, enlarged and differentiated.•TBS34N mice had enhanced human mature T- and B-cells in mouse spleen.•BR3+ cells and AID+ B-cells were enriched in the spleen of TBS34N mice.•Ag-specific hIgG Abs were secreted into the sera of all TBS34N mice upon immunization.

We previously generated humanized TB34N mice that received human fetal thymus (T), bone tissue (B) and fetal liver-derived (FL)-CD34+ cells (34) in immunodeficient, NOD/SCID IL2Rγnull (N) mice. Although humanized TB34N mice had excellent hematopoiesis, here, we sought to further improve this model by additional transplantation of human spleen tissue (S) as a secondary hematopoietic tissue (TBS34N). The human spleen grafts were enlarged and differentiated into a similar morphology of adult humans, including follicular lymphoid structures with T- and B-cells. The TBS34N mice mimicked mature human immune system (HIS): mature T- and B-cells and follicular dendritic cells; activated germinal center B-cells expressing CD71, BR3+ cells, memory B-cells and activation-induced cytidine deaminase+ B-cells; CD138+ plasma cells were enriched in the mouse spleen. HBsAg-specific hIgG antibodies were secreted into the sera of all TBS34N mice upon immunization with HBsAg. Taken together, the humanized TBS34N mice improved mature HIS and achieved adaptive antibody responses.