A multiple transgenic mouse model with a partially humanized activation pathway for helper T cell responses

Mice expressing human CD4 and human MHC II molecules provide a valuable model both for the investigation of the immunopathogenetic role of human autoantigens and for the development of therapeutic strategies based on modulating helper T cell activation in vivo. Here we present a novel mouse model expressing HLA-DR17 (a split antigen of HLA-DR3) together with human CD4 in the absence of murine cd4 (CD4/DR3 mice). Human CD4 accurately replaces murine cd4 within T cells. In particular, the preservation of cd8(+) and CD4(+) T cell subsets distinguishes CD4/DR3 mice from other multiple transgenic models in which the alternative T cell subsets are fundamentally disturbed. Moreover, human CD4 is also faithfully expressed on antigen presenting cells such as dendritic cells and monocyte/macrophages, so that the overall transgenic CD4 expression pattern resembles very closely that of humans. HLA-DR3 expression in the thymus correlates very closely to that of mouse MHC II. In contrast, only 70% of mouse MHC II positive cells in spleen, lymph node, and peripheral blood coexpress HLA-DR3. No significant bias was found with regard to particular leucocytes in this respect. The stimulation of helper T cells clearly depends on the interaction between the human transgene products, since mAbs to HLA-DR and/or CD4 completely blocked in vitro recall responses to tetanus toxoid. CD4/DR3 mice represent a partially humanized animal model which will facilitate studies of DR3-associated autoimmune responses and the in vivo determination of the therapeutic potential of mAbs to human CD4.