Modulation of F1 cytotoxic potentials by GvHR: suppression of cytotoxic T cell responses of F1 mice correlates with F1 inability to resist the proliferation of GvHR-inducing parental T lymphocytes.

Graft-vs-host reaction (GvHR) induced in (C57BL/6 x DBA/2)F1 mice by injection of C57BL/6, but not DBA/2 spleen cells, strongly suppressed the subsequent in vitro CTL responses of spleen cells from the F1 mice to allogeneic as well as trinitrophenyl-modified F1 (TNP-self) stimulator lymphocytes. In the four additional combinations of F1 mice studied ((AKR/J X C57BL/6)F1, H-2k/b; (C3H/He X C57BL/6)F1, H-2k/b; (BALB/c X C57BL/6)F1, H-2d/b; and (BALB/c X AKR/J)F1, H-2d/k), injection of parental C57BL/6 spleen cells into H-2k/b or H-2d/b mice always resulted in the abrogation of the subsequent CTL responses of the F1 hosts; whereas GvHR induced in H-2k/b and H-2 d/k by AKR/J lymphocytes, in H-2k/b by C3H/He lymphocytes, or in H-2d/b and H-2a/k by BALB/c lymphocytes had no appreciable effect on the subsequent CTL responses of the respective F1 hybrid mice. In addition, C57BL/6 → F1 (GvHR) spleen cells exerted an active suppressive effect on the in vitro CTL responses of normal F1 spleen cells to third-party alloantigens when the spleen cells from normal and injected mice were co-cultured. The suppressor cells were nonadherent, not retained on a Sephadex G-10 column, sensitive to mito-mycin-C treatment, inactivated by treatment with anti-Thy-1 but not anti-asialo GM1 antibodies plus C, and enriched in a nylon-passed fraction (suppressor T cells). Closer examination of GvHR of (AKR/J x C57BL/6)F1 mice induced with either parental AKR/J or C57BL/6 lymphocytes demonstrated that in the spleen of F1 mice that received C57BL/6 lymphocytes, T lymphocytes were extensively replaced by donor-type C57BL/6 cells and that these donor T lymphocytes exerted the suppression of CTL responses, whereas those in F1 mice that received AKR/J lymphocytes were all recipient-type F1 cells. These results indicate that GvHR-associated suppression of CTL potentials has a striking correlation with the in vivo F1 natural resistance (hybrid resistance [HyR]) to parental bone marrow (BM) transplants; i.e., both phenomena are seen only in strain combinations of C57BL/6 → F1 systems, out of all the F1 hybrid crosses from H-2b, k, d parents presently studied. Therefore, it is noteworthy that homozygous H-2b, but not H-2k, T lymphocytes invade and proliferate in the spleens of unirradiated normal H-2k/b F1 mice, whereas in the in vivo HyR system using irradiated F1 recipients, H-2 b but not H-2k BM transplants are rejected by the same H-2k/b F1 mice.