Antigen-specific human immunoglobulin production in SCID mice transplanted with human peripheral lymphocytes is dependent on CD4+ CD45RO+ T cells

Severe combined immunodeficient (SCID) mice, lacking mature T and B cells and virtually devoid of endogenous serum immunoglobulins, spontaneously produce large amounts of human immunoglobulin after transplantation with human peripheral blood lymphocytes (PBL). Moreover, after immunization with antigen an active immune response resulting in a production of specific antibodies can be induced. Here we report that human T cells must be co-transplanted with B cells into the SCID mice for immunoglobulin production to occur. Resting human B cells could be activated to immunoglobulin production in the absence of human monocytes and a specific antibody response to tetanus toxoid (TT) could be induced, suggesting that the human B cells could present antigen to T cells in the SCID environment. Production of human immunoglobulins, as well as specific antibodies, was obtained only if CD4+ T cells of the memory phenotype, i.e. expressing CD45RO, were present. No human immunoglobulin, either of IgM or of IgG isotype, was found in SCID sera if mice were co-transplanted with human B cells and CD45RA expressing CD4+ T cells. However, FACS analysis revealed that the transplanted CD45RA+ cells became activated and differentiated towards CD45RO+ cells within 1-2 weeks. These cells also gained the lymphokine gene expression pattern associated with CD45RO+ cells, as demonstrated by polymerase chain reaction (PCR) analysis, and could support immunoglobulin production in SCID mice transplanted with fresh B cells. In fact, after differentiation of CD4+ CD45RA+ T cells towards expression of CD45RO, either in vivo in the SCID mouse or in vitro, these cells could interact with and activate human B cells to immunoglobulin production. Furthermore, in vitro activated and differentiated CD4+ CD45RA+ T cells from vaccinated donors were also able to support production of TT-specific antibodies provided the antigen was administered.