THE STRENGTH OF CELL-MEDIATED XENOGRAFT REJECTION IN THE MOUSE IS DUETO 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 v itro studies have suggested that this CD4+ response is to xenogeneic a ntigens that are presented indirectly. The present studies were carrie d out in order to determine whether the strength of cell-mediated xeno graft rejection in vivo is dependent on the CD4+ indirect response. We grafted pig skin onto mice that express class II MHC antigens only on their thymic epithelial cells (II-4+ mice). These mice have normal nu mbers of functional peripheral CD4+ T cells; however they lack class I I MHC expression on their antigen presenting cells and are thus incapa ble of mounting a CD4+ T cell-mediated indirect response. Xenograft su rvival was prolonged on these mice. Furthermore, administration of cyc losporine and anti-CD8 monoclonal antibodies to II-4+ recipients prolo nged xenograft survival to at least the same extent as allograft survi val, demonstrating that the strength of cell-mediated xenograft reject ion resides in the CD4+ indirect response. Despite the increased survi val time, xenograft rejection still occurred in the absence of the ind irect pathway. Depletion of the II-4+ recipients of their CD4+ T cell population prolonged xenograft survival even further, suggesting the p resence of a weaker CD4+ direct mechanism which was virtually undetect able in vitro.