PROFOUND ATROPHY OF THE BONE-MARROW REFLECTING MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-RESTRICTED DESTRUCTION OF STEM-CELLS BY CD4+ CELLS

The effector functions of CD4(+) cells in vivo are presumed to reflect a combination of lymphokine-mediated bystander reactions and direct c ytotoxic T lymphocyte activity. To assess the relative importance of t hese two mechanisms, we studied the effects of transferring small dose s of purified unprimed CD4(+) cells to lightly irradiated (600 cGy) re cipients expressing major histocompatibility complex class II (Ia) dif ferences. Within the first week after transfer, the host marrow was ra pidly repopulated with hemopoietic cells. Thereafter, however, the don or CD4(+) cells caused massive destruction of hemopoietic cells, both in marrow and spleen. Marrow aplasia did not affect stromal cells and was prevented by coinjecting donor but not host bone marrow. The use o f allotypic markers and fluorescence-activated cell sorter analysis in dicated that the destructive effects of CD4(+) cells were directed sel ectively to host Ia(+) hemopoietic cells, including stem cells; donor hemopoietic cells and Ia(-) host T cells were spared. No evidence coul d be found that the ongoing destruction of host cells impaired the cap acity of donor stem cells to repopulate marrow, spleen, or thymus. Mor eover, CD4(+) cells failed to destroy host-type hemopoietic cells from Ia-deficient mice. Tissue destruction by CD4(+) cells thus did not se em to reflect a bystander reaction. We conclude that, under defined co nditions, CD4(+) cells can manifest extremely potent Ia-restricted CTL activity in vivo, probably through recognition of covert Ia expressio n on stem cells and/or their immediate progeny.