‘Self’ tolerance in a parent → F 1 radiation chimera

Abstract

The extent to which T cell immune tolerance to self tissue antigens is acquired during intrathymic development, or also may occur elsewhere in the animal, remains unclear. Experiments have been designed to explore this using allogeneic hematopoietic radiation chimeras in which thymectomized CB6F 1 (H-2 b/d) host mice were engrafted with day 16 C57BL/6 (H-2 b) fetal thymus tissues, irradiated with 950 rad 3 weeks later, and reconstituted with day 14 C57BL/6 fetal liver cells. Chimeras constructed in this manner had thymus grafts which developed with normal structure and cellularity as determined from histological sections, and had normal proportions of CD4 +8 − and CD4 −8 + peripheral T cells of donor H-2 b origin. Mice showed no signs of acute or chronic GVHD when followed for six months and, although T cells from chimeras were non-reactive to donor (H-2 b) or host (H-2 d) MHC, they responded to third party (H-2 k) alloantigens in primary mixed-lymphocyte reactions. To determine whether tolerance might have been induced by radioresistant host hematopoietic cells, mice were treated with anti-I-A d monoclonal antibody after irradiation and fetal liver cell transfer. The pattern of alloreactivity of T cells from those animals closely resembled that of non-antibody treated mice, suggesting that tolerance to MHC expressed within the host probably was not due to radioresistant class-II-bearing cells in chimeras. These findings imply that immune tolerance to self antigens can be controlled at sites outside the thymus, and they provide further evidence that allogeneic chimeras can be constructed when elimination of mature T cells from the donor hematopoietic pool has been effectively achieved.