The strength of cell-mediated xenograft rejection in the mouse is due to the CD4+ indirect response

: Previous studies have shown that CD4+ T cells are responsible for the great strength of cell‐mediated xenograft rejection in the mouse. In vitro studies have suggested that this CD4+ response is to xenogeneic antigens that are presented indirectly. The present studies were carried out in order to determine whether the strength of cell‐mediated xenograft rejection in vivo is dependent on the CD4+ indirect response. We grafted pig skin onto mice that express class 11 MHC antigens only on their thymic epithelial cells (II‐4+ mice). These mice have normal numbers of functional peripheral CD4+ T cells; however they lack class II MHC expression on their antigen presenting cells and are thus incapable of mounting a CD4+ T cell‐mediated indirect response. Xenograft survival was prolonged on these mice. Furthermore, administration of cyclosporine and anti‐CDS monoclonal antibodies to II‐4+ recipients prolonged xenograft survival to at least the same extent as allograft survival, demonstrating that the strength of cell‐mediated xenograft rejection resides in the CD4+ indirect response. Despite the increased survival time, xenograft rejection still occurred in the absence of the indirect pathway. Depletion of the II‐4+ recipients of their CD4+ T cell population prolonged xenograft survival even further, suggesting the presence of a weaker CD4+ direct mechanism which was virtually undetectable in vitro.