On the immunocompetence of H-2 incompatible irradiation bone marrow chimeras.

Abstract

Abstract The immunocompetence of irradiation bone marrow chimeras formed by reconstituting lethally irradiated homozygous recipient mice with T cell-depleted lympho-hemopoietic stem cells from H-2 incompatible donors was studied with respect to the chimeras’ capacity to generate in vivo H-2-restricted antiviral cytotoxic T cells, to express delayed-type hypersensitivity reactions, and to eliminate virus, or in vitro to generate alloreactive cytotoxic T cells. Allogeneic irradiation chimeras, in general, rarely survived 2 to 4 weeks; the few survivors were often only partially reconstituted. An H-2 typing method was developed that exploits the capacity of surviving recipient cells to induce alloreactivity in a mixed lymphocyte culture; the sensitivity of this method is about 10 times better than conventional serologic typing and can detect one allogeneic cell in 125. When both typing methods were employed, only very rare allogeneic chimeras did not contain detectable recipient lymphocytes. Such fully reconstituted H-2k → H-2b chimeras were incapable of clearing virus, expressing delayed-type hypersensitivity reactions, and did not generate restricted virus-specific cytotoxic T cells in vivo or alloreactive T cells in vitro. In contrast, chimeras with even minor numbers of host lymphocytes generated alloreactive T cells but sometimes failed to generate restricted virus-specific T cells; this may reflect the presence of suppressive mechanisms directed against the T cell receptor for the restricting H-2 antigen. A few (H-2b → H-2k) or (H-2b → H-2d) chimeras showed low but detectable antiviral cytotoxic T cells restricted to the donor H-2 and generated alloreactive T cells; it is unclear whether the differentiation of T cells restricted to the donor H-2 is mediated by incomplete removal of T cells from the reconstituting stem cells or is made possible by cross-reactivities of restriction specificities. All allogeneic irradiation chimeras that expressed alloreactivity were tolerant to both host and donor H-2. The immunocompetence of allogeneic irradiation chimeras is at least 10- to 30-fold less than in H-2 compatible chimeras. Therefore, from the point of view of survival of acute infectious disease, allogeneic irradiation chimeras were generally immunodeficient. The finding that in some haplotype combinations fully reconstituted allogeneic irradiation chimeras did not generate restricted or alloreactive T cells suggests that alloreactivity and restricted T cell activity do not differentiate independently, but rather in parallel; therefore, alloreactivity may be mediated by restricted T cells via receptors that cross-react with environmental antigens.