Enhancement of MHC class I-stimulated alloresponses by TNF/TNF receptor (TNFR)1 interactions and of MHC class II-stimulated alloresponses by TNF/TNFR2 interactions

In vivo TNF inhibition has been observed to ameliorate the disease process attributed to T cell-dependent immune responses such as those generated dur ing graft-vs.-host disease. The present studies were designed to evaluate w hether TNF/TNF receptor (TNFR)1 and TNF/TNFR2 interactions were involved in the generation of allospecific T cell responses. Splenic lymphocyte popula tions were obtained from TNFR1- or TNFR2-deficient B6 mice and from control B6 mice. These responder cells were cultured with irradiated MHC class II- disparate B6.C-H-2(bm12) (bm12) or MHC class I-disparate B6.C-H-2(bm1) (bm1 ) or irradiated syngeneic stimulator cells for 3 days before assay of [H-3] thymidine incorporation. IL-2 levels of the mixed lymphocyte culture (MLC) supernatants were assessed by enzyme-linked immunosorbent assay. With MHC c lass It-disparate bm12 stimulator cells, a significant reduction in T cell proliferation was observed utilizing TNFR2-deficient CD4(+) responder T cel ls, but not when using TNFR1-deficient CD4(+) responder T cells. A signific ant decrease in proliferation of TNFR1-deficient CD8(+) responder cells, bu t not of TNFR2-deficient CD8 responder T cells was observed after stimulati on with MHC class I-disparate bm1 stimulator cells. IL-2 levels were lower in MLC utilizing MHC class I stimulators and TNFR1-deficient responders or MHC class II stimulators and TNFR2-deficient responders. These results indi cate that TNF/TNFR2 interactions promote MHC class Ii-stimulated allorespon ses, while TNF/TNFR1 interactions promote MHC class I-stimulated allorespon ses.