HLA‐G has a concentration‐dependent effect on the generation of an allo‐CTL response

Abstract

SUMMARYHuman leucocyte antigen (HLA) -G is expressed on trophoblast cells during pregnancy, suggesting a role in protection of the semiallogeneic fetus. Published data suggest that HLA-G protects a cell against natural killer cell lysis. It has been hypothesized that HLA-G may also protect the fetus by preventing allo-cytotoxic T lymphocyte (CTL) responses. To test this hypothesis, we assayed the effects of various concentrations of puri®ed HLA-G on CTL response in a mixed lymphocyte culture (MLC) system. We found that concentrations i 0 . 1 mg/ml of HLA-G suppressed the allo-CTL response by 30±100% over the control, but, paradoxically, concentrations of 0 . 01±0 . 05 mg/ml of HLA-G augmented the allo-CTL response by 25±50% over the control. Concentrations j 0 . 001 mg/ml HLA-G had no effect. Addition of HLA-G to preprimed allo-CTL effector cells did not affect their killing ability. Allo-CTL suppressive doses of HLA-G induced a T helper type 2 (Th2) cytokine response, whereas allo-CTL-enhancing doses of HLA-G induced a Th1-type cytokine response. HLA-G puri®ed from ®rst-trimester placenta does not affect allo-proliferative responses nor does it alter the percentage of CD4 + or CD8 + T cells in MLCs. These ®ndings support a potential role for HLA-G-mediated suppression of allo-CTL formation in normal pregnancies. In addition, the effects observed at lower concentrations of HLA-G may have interesting implications for the condition of pre-eclampsia in which concentrations of this HLA class I molecule are reduced.

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

“…Specifically, we have identified the novel T cell epitope HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] , which elicits effective antitumor CD4 C T cell responses against HLA-G-positive tumors. Although emphasis has been put on CD8 C CTLs for tumor immunotherapy because of their direct cytotoxicity against tumor cells, CD4 C T cells also play an important role in antitumor immunity.…”

“…Also, HLA-G peptide vaccine would not be suitable for autoimmune patients because it could aggravate their disease in instances where HLA-G is expressed. 25 Homologous sequences very similar to HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] were found on the classical MHC-I HLA-A, -B and -C molecules (Table S1). Nevertheless, the HLA-G 26-40 -specific CD4 C T cells did not crossreact with these analogous peptides.…”

“…Nevertheless, the HLA-G 26-40 -specific CD4 C T cells did not crossreact with these analogous peptides. This suggests that the unique residues in HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] (two alanines at position 34 and 35) may play an important role in binding to MHC-II or as T cell receptor contact residues. Whichever the cause is for the lack of cross- Figure 6.…”

“…Experiments were performed in duplicate. reactivity, our results and the restricted expression of HLA-G indicate that T cell responses to HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] would not results in widespread autoimmunity when used in the clinical setting. Moreover, we found a substantial amount of IFNg production from patient PBMCs by HLA-G [25][26][27][28][29][30][31][32][33] peptide stimulation suggesting that this peptide can potentially induce Th1 rather than regulatory T cells.…”

“…4A, the HLA-G-specific CD4 C T cell clones directly recognized the HLA-DR subtype-matched tumor cells expressing HLA-G when the cell lines were treated with IFNg (Lu65, did not have to be treated with IFNg, to be recognized by the CD4 C T cell clones). The T cell response against the tumor cells was effectively inhibited by anti-HLA-DR mAb, indicating that HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was presented in the context of HLA-DR. Treatment with 5-AZA increased the T cell responses to the HLA-G-expressing tumors except for Lu65 (Fig.…”