The interaction defect of accessory molecules is responsible for the poor ex vivo response to human antigens of mouse T helper cells

Mouse T cells fail to respond to xenogeneic pig and human antigens using the direct antigen-presenting pathway. The poor response by mouse CD8 cells is because of multiple defects in the molecular interactions between mouse CD8 cells and xenogeneic antigen-presenting cells (APCs). Using human CD4/DR3⁺, mouse CD4^-/major histocompatibility complex (MHC) class II^- mice, we investigated the defects in molecular interaction responsible for the poor response to xenogeneic antigens by naïve mouse CD4⁺ cells. Mouse CD4 cells failed to respond to human leucocyte antigen (HLA)-DR3 expressed on mouse APCs but developed a strong response to alloantigens, indicating a defect in the interaction between mouse CD4 and HLA-DR3 molecules. Human CD4⁺/mouse CD4^- mouse T cells respond poorly to human and pig APCs but not allogeneic APCs, indicating that accessory molecular interactions are deficient across highly separated species. Adding mouse interleukin-2 (IL-2) to the mixed lymphocyte reaction system did not improve the poor response to human or pig antigens by mouse or human CD4⁺/mouse CD4^- mouse T cells. Therefore, multiple molecular interactions deficient between mouse CD4 cells and human or pig APCs may lead to the poor response to xenogeneic antigens by naïve mouse CD4 cells.