Protection from T helper cell-mediated graft-versus-host disease by the presence of an MHC class I alloantigen is associated with perturbation of MHC class II-restricted responses by class I-derived peptides

Lethal graft-vs-host disease (GVHD) develops after transfer of CTL-depleted spleen and bone marrow cells from C57BL/6 (B6) mice to irradiated MHC class II disparate (B6×bm12)F₁ recipients. Onset of lethal GVHD is significantly delayed in (bm1×bm12)F₁ recipients of the same donor inoculum despite the additional MHC class I disparity (H-2K^bm1). To investigate the basis of this protective effect, hybridomas were generated from T cells activated in vivo during GVHD in both strain combinations. T cells from B6→(B6×bm12)F₁ mice generated a significantly higher frequency of B6.C-H-2^bm12 (bm12)-specific T hybridomas (110/178, 62%) than T cells from B6→(bm1→bm12)F₁ mice (102/218, 47%). Some bm12-specific T hybridomas exhibited lesser responses to (bm1×bm12)F₁ than to (B6×bm12)F₁ APC. Moreover, bm1 peptides spanning a 14-amino acid region that includes the three amino acids that differ from H-2K^b were found to inhibit responses of some bm12-specific T hybridomas and to decrease significantly responses of splenic B6 CD4⁺ T cells to bm12 APC. Notably, the frequency of bm12-reactive hybridomas susceptible to inhibition by bm1 peptides generated from B6→(B6×bm12)F₁ mice was significantly greater than that generated from B6→(bm1×bm12)F₁ mice. Additional analysis using L cell transfectants indicated that hybridomas responding to the bm12 mutation at position 70 alone were rarely inhibited by bm1 peptides. The data indicate that expression of bm1-derived peptides can influence the frequency and spec-ificity of alloreactive CD4⁺ T cells stimulated in vivo and thus may alter the course of GVHD.