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

Abstract

In vivo TNF inhibition has been observed to ameliorate the disease process attributed to T cell‐dependent immune responses such as those generated during graft‐vs.‐host disease. The present studies were designed to evaluate whether TNF/TNF receptor (TNFR)1 and TNF/TNFR2 interactions were involved in the generation of allospecific T cell responses. Splenic lymphocyte populations 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‐2bm12 (bm12) or MHC class I‐disparate B6.C‐H‐2bm1 (bm1) or irradiated syngeneic stimulator cells for 3 days before assay of [3H]thymidine incorporation. IL‐2 levels of the mixed lymphocyte culture (MLC) supernatants were assessed by enzyme‐linked immunosorbent assay. With MHC class II‐disparate bm12 stimulator cells, a significant reduction in T cell proliferation was observed utilizing TNFR2‐deficient CD4+ responder T cells, but not when using TNFR1‐deficient CD4+ responder T cells. A significant decrease in proliferation of TNFR1‐deficient CD8+ responder cells, but not of TNFR2‐deficient CD8 responder T cells was observed after stimulation 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 indicate that TNF/TNFR2 interactions promote MHC class II‐stimulated alloresponses, while TNF/TNFR1 interactions promote MHC class I‐stimulated alloresponses.

TNF Enhances CD4+ T Cell Alloproliferation, IFN-γ Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms

“…We have previously observed that TNF/TNFR2 interactions on responder CD4 ϩ T cells are critical for optimal alloproliferation and Th1 cytokine responses by T cells in response to alloantigenic stimuli in vitro or in vivo during intestinal GVHD (30). As TNF has been reported to stimulate IL-12 production by macrophages (6), these earlier results suggested that TNF may amplify Th1 cytokine responses by an indirect effect on IL-12 production.…”

“…Triplicate wells of control B6 or B6.IL-12R Ϫ/Ϫ responder spleen cells (3 ϫ 10 5 ) were cultured with irradiated MHC class II disparate bm12 (3 ϫ 10 5 ) or irradiated syngeneic stimulator cells (3 ϫ 10 5 ) in the presence or absence of a chimeric TNF inhibitor protein (0.5 g/ml) for 3 days before assay of [ 3 H]thymidine incorporation, as previously described (30).…”

“…Plates were coated with 100 l/well of the diluted capture Ab for the cytokine during overnight incubation at 4°C, and then after washing to remove excess capture Ab, between 50 and 100 l of the supernatants or medium was added to triplicate wells and incubated for 2 h. After washing, the enzyme reagent was added to the wells and incubated, substrate solution was added and incubated, and the stop solution was added. The OD was read at 450 nm, as previously described (30). The recommended lowest dilution of the IL-4 standard used in the ELISA from BD PharMingen assay is 7.8 pg/ml.…”

“…TNF blockade in alloresponses by wild-type mouse T cells is associated with a decrease in Th1 responses (12,30). Additional studies were conducted to determine whether the IFN-␥ production is decreased after TNF blockade in MHC class II disparate MLC using B6.IL-12R Ϫ/Ϫ splenic T cells.…”

Relationship between TNFA, TNFB and TNFRII gene polymorphisms and outcome after unrelated hematopoietic cell transplantation in a Chinese population

“…34,35 TNFRII promotes T-cell proliferation and MHC class II-stimulated alloresponses. 36 TNF-TNFRII interactions are critical for the development of aGVHD in animal models and recombinant human soluble TNFRII fusion protein is currently used to treat steroid refractory GVHD. 37,38 Our study indicates that transplants involving recipients and/or donors with TNFRII 196 T/T genotype had a higher risk of aGVHD, though the influence was not TNFA, TNFB and TNFRII gene polymorphisms and allo-HSCT H Xiao et al significant in an HLA-matched cohort and using multivariate analysis.…”