Cutting edge: requirement of class I signal sequence-derived peptides for HLA-E recognition by a mouse cytotoxic T cell clone.
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The human nonclassical MHC class I molecule HLA-E has recently been shown to act as a major ligand for NK cell inhibitory receptors. Using HLA-E-expressing transgenic mice, we produced a cytotoxic T cell clone that specifically recognizes the HLA-E molecule. We report here that this T cell clone lyses HLA-E-transfected RMA-S target cells sensitized with synthetic class I signal sequence nonamers. Moreover, this T cell clone lyses human EBV-infected B lymphocytes, PHA blasts, and PBL, formally demonstrating the surface expression of HLA-E/class I signal-derived peptide complex on human cells. Furthermore, these data show that HLA-E complexed with class I signal sequence-derived peptides is not only a ligand for NK cell inhibitory receptors, but can also trigger cytotoxic T cells (CTL). (+info)
Trophoblast cell line resistance to NK lysis mainly involves an HLA class I-independent mechanism.
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The lack of classical HLA molecules on trophoblast prevents allorecognition by maternal T lymphocytes, but poses the problem of susceptibility to NK lysis. Expression of the nonclassical class I molecule, HLA-G, on cytotrophoblast may provide the protective effect. However, the class I-negative syncytiotrophoblast escapes NK lysis by maternal PBL. In addition, while HLA-G-expressing transfectants of LCL.721.221 cells are protected from lymphokine-activated killer lysis, extravillous cytotrophoblast cells and HLA-G-expressing choriocarcinoma cells (CC) are not. The aim of this work was therefore to clarify the role of HLA class I expression on trophoblast cell resistance to NK lysis and on their susceptibility to lymphokine-activated killer lysis. Our results showed that both JAR (HLA class I-negative) and JEG-3 (HLA-G- and HLA-Cw4-positive) cells were resistant to NK lysis by PBL and were equally lysed by IL-2-stimulated PBL isolated from a given donor. In agreement, down-regulating HLA class I expression on JEG-3 cells by acid treatment, masking these molecules or the putative HLA-G (or HLA-E) receptor CD94/NKG2 and the CD158a/p58.1 NKR with mAbs, and inducing self class I molecule expression on JAR cells did not affect NK or LAK lysis of CC. These results demonstrate that the resistance of CC to NK lysis mainly involves an HLA class I-independent mechanism(s). In addition, we show that the expression of a classical class I target molecule (HLA-B7) on JAR cells is insufficient to induce lysis by allospecific polyclonal CTL. (+info)
Depletion of alloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukemia and antiviral activity.
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The success of bone marrow transplantation (BMT) from HLA-disparate donors depends on the development of new strategies able, on one hand, to efficiently prevent graft-versus-host disease (GVHD) and, on the other hand, to protect leukemic patients from relapse and infections. Using an immunotoxin (IT) directed against the alpha chain (p55) of the human interleukin-2 receptor (RFT5-SMPT-dgA), we previously showed that it is possible to kill mature T cells activated against a specific HLA complex by a one-way mixed lymphocyte culture (MLC). The present study was performed to investigate whether this protocol of allodepletion affects the capacity of residual T cells to display antileukemia and antiviral activity evaluated by limiting dilution assays (LDA), measuring the frequency of cytotoxic T-lymphocyte precursors (CTLp) directed against autologous leukemic blasts (LB) and cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-infected target cells. Antileukemia activity was evaluated in peripheral blood mononuclear cells (PBMC) of 3 patients treated for acute myeloid leukemia who had developed a high frequency of LB-reactive CTLp after either autologous or allogeneic BMT. Results demonstrate that (1) depletion with RFT5-SMPT-dgA efficiently inhibited MLC; (2) fresh PBMC of patients yielded a high frequency of LB-reactive CTLp comparable to that of the mock-treated PBMC; and (3) effector cells obtained after allodepletion fully retained the capacity to lyse pretransplant LB. By contrast, the frequency of CTLp directed against patient's pretransplant BM remission cells was always undetectable. Data obtained in 4 healthy donors showed that specifically allodepleted T cells recognized and killed autologous CMV-infected fibroblasts and autologous EBV-B-lymphoblastoid cell lines. In conclusion, our data indicate that allodepletion using RFT5-SMPT-dgA efficiently removed alloreactive cells, while sparing in vitro antileukemic and antiviral cytotoxic responses. (+info)
Immune function in ankylosing spondylitics and their relatives: influence of disease and HLA B27.
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So as to distinguish the separate influences of ankylosing spondylitis (AS) and possible HLA B27 associated immune response genes on immune response patterns, a battery of immunological tests were performed on fourteen patients with AS and their first-degree relatives. Previously unrecognized AS was detected by clinical and radiological means. Individuals with ankylosing spondylitis had significantly higher serum IgG and IgA concentrations than both their B27 positive and B27 negative relatives. B27 positive relatives had significantly lower phytohaemagglutinin (PHA) lymphocyte transformations than B27 negative relatives (P less than 0.01), while there was no difference between the ankylosing spondylitic and B27 positive groups. Antibody titres to Streptokinase/Streptodornase were significantly higher in the B27 positive individuals, with or without AS, than their B27 negative relatives (P less than 0.005 and P less than 0.02 respectively). These results show that serum immunoglobulin differences were associated with disease, while differences in PHA stimulation and varidase antibody titres were associated with the B27 antigen. These findings may indicate the presence of HLA associated immune response genes including those involved with reactions to a particular antigenic component of Streptokinase/Streptodornase. (+info)
Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis.
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Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Recent demonstration of an association between transferrin receptor (TfR) and HFE, a major histocompatibility complex class I-like molecule that has been implicated to play a role in hereditary hemochromatosis, further strengthens the notion that HFE is involved in iron metabolism. Herein we show that TfR is required for and controls the assembly and the intracellular transport and surface expression of HFE. Because surface-expressed HFE and TfR remain firmly associated physically, only the fraction of TfR that is associated with HFE during biosynthesis is affected functionally. Moreover, we show that HFE binding reduces the number of functional transferrin binding sites and impairs TfR internalization, thus reducing the uptake of transferrin-bound iron. Thus, iron homeostasis is indirectly regulated by HFE, a negative modulator of TfR. (+info)
p205 is a major target of autoreactive T cells in rheumatoid arthritis.
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OBJECTIVE: The p205 autoantigen and interleukin-2 (IL-2) function synergistically to stimulate T lymphocytes from patients with rheumatoid arthritis (RA), and a p205-derived amino acid sequence is identical to an immunoglobulin sequence located within a domain that is reactive with rheumatoid factors (RF). This study was conducted to analyze in detail the T cell immune response against p205 and to investigate whether immunity to p205 may play a role in T cell-mediated immunopathology in active RA. METHODS: Cibachron blue, protein A-Sepharose, and gel filtration on Sephacryl were used successively to enrich p205 from synovial fluid (SF). T lymphocytes from RA patients were isolated from the peripheral blood (PB), lymph nodes, and SF, and p205 and peptides derived from known sequences were assessed by T cell proliferation assays in the presence of IL-2. RESULTS: P205-specific proliferation of T cells was observed in PB as well as in SF. When p205 was isolated from RA SF, proliferation of RA T cells peaked on day 3. With p205 purified from SF from trauma patients, there was a significant shift of the maximum T cell proliferation to day 8. T cells were of CD4 or CD8 phenotype, and B cells did not proliferate to a significant degree. The T cell response to p205 was always higher for SF mononuclear cells (SFMC) compared with PBMC (P < 0.001). In 1 RA patient who underwent repeated leukapheresis, this led to a reproducible decline in p205-specific T cell proliferation to control levels. PB T cells specifically proliferating in response to p205 were detected in 20 of 32 RA patients (63%). Of 26 patients with other inflammatory rheumatic diseases, only 1 showed a minor response to p205, while normal donors did not demonstrate a significant T cell proliferation. A synthetic p205-derived peptide, with an amino acid sequence identical to an immunoglobulin sequence located in the area where RF binds, was reactive with T cells from RA patients. CONCLUSION: P205 appears to be a major target of autoreactive T cells in RA. P205-specific T cells are primed and more abundant at the site of inflammation. As a T cell target in RA, p205 may well be an antigen involved in the initiation of RF production. (+info)
IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes.
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HLA-G plays an essential role in feto-maternal tolerance by inhibiting lysis by maternal NK cells. The factors that allow tissue-specific activation of HLA-G gene expression in trophoblasts remain to be characterized. We investigated the potential effect of IL-10, a cytokine which is secreted in placenta, on HLA-G gene transcription in trophoblasts. Using Northern blot, RNase protection assay and RT-PCR analysis, we demonstrated that IL-10 enhances steady-state levels of HLA-G transcription in cultured trophoblast cells. We further tested the effect of IL-10 on HLA-G gene transcription and protein expression in peripheral blood monocytes, showing that IL-10 can up-regulate HLA-G cell surface expression in this cell type. This effect of IL-10 is selective, since classical MHC class I products and MHC class II are down-regulated in monocytes following IL-10 treatment. Induction of HLA-G expression by IL-10 on monocytes may thus play a role in down-regulation of the immune response. We propose that IL-10 secretion by trophoblasts during pregnancy may also influence the HLA class I expression pattern at the feto-maternal barrier, thus protecting the fetus from rejection. This should be taken into consideration in the design of treatment for pathologies of pregnancy. (+info)
Endometriosis and unexplained recurrent spontaneous abortion: pathological states resulting from aberrant modulation of natural killer cell function?
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The observation that natural killer (NK) cell activity is abnormally low in endometriosis patients and abnormally high in women with otherwise unexplained recurrent spontaneous abortion represents, at present, an intriguing curiosity. There is evidence suggesting that these conditions are associated with an opposite regulation of NK cell behaviour. This review discusses these observations and potential relationships. (+info)