HLA-G and lymphoproliferative disorders Amiot, Laurence; Friec, Gaëlle Le; Sebti, Yasmine ...
Seminars in cancer biology,
10/2003, Letnik:
13, Številka:
5
Journal Article
Recenzirano
The immunomodulatory properties of the HLA-G molecule explain its relevance in malignancies. Our investigations in lymphoproliferative disorders show (i) a frequent and variable distribution of ...alternatively spliced HLA-G mRNA isoforms, (ii) a rare cell surface expression in diffuse large cell lymphomas with HLA class I loss in half of cases, and (iii) an increased serum level of sHLA-G in half of cases. The potential role of the microenvironment and/or tumoral process in HLA-G expression is discussed in the light of these data. HLA-G rather through its soluble isoform might provide a new way of immune evasion for lymphoid proliferations.
Abstract
Many studies including human genetics have implicated IL10-producing cells as key in limiting immune pathology during infection and in preventing autoimmunity. Here we show that the ...complement regulator CD46 regulates IL10 production in an IL2-dependent fashion. More specifically, CD3/CD46-activation of human CD4+ T cells in low IL2 induces strong IFNγ secretion, whereas increasing IL2 induces a ‘switch’ to immunosuppressive Tr1-like cells that are initially IFN-γ+/IL10+, and then IL-10+. We propose that CD46 activation initially promotes antimicrobial Th1 effector responses, while expansion of this response increases local IL2, promoting a CD46-dependent switch to IL10-mediated immunoregulation. The significance of this in vivo is supported by the failure of CD3/CD46-activated CD4+ T cells from rheumatoid arthritis patients to switch to the IL10+ state, producing ≥20-fold more IFNγ than IL10. IL10-switching of CD4+ T cells is mediated by the CYT-1 isoform of the alternatively spliced cytoplasmic tail of CD46. Interestingly, human γδ T cells, whose importance to the early effector phase of immune responses is increasingly apparent, express predominantly the CYT-2 isoform of CD46. Thus, they do not produce IL10 in response to TCR/CD46 co-engagement, but rather significantly decrease their IFNγ and TNFα production. Thus, we propose that CD46 uses distinct molecular mechanisms to regulate unconventional and conventional T cells across the span of the immune response.
CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ ...(IFN-γ)-secreting effector T helper type 1 (T(H)1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4(+) T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate T(H)1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon γ (IFN ...γ)-secreting effector T helper type 1 (T.sub.H1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4.sup.+ T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate T.sub.H1 responses in vitro and in vivo, which suggested that CD46- Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human leukocyte antigen (HLA‐G), a class Ib major histocompatibility complex molecule, is potentially relevant in the immune response through its various immune cell functions. Its expression noticed ...in some malignancies has also been shown on macrophages and dendritic cells (DC) in tumoral and inflammatory diseases. As DC constitute a key component in the immune response, this work aimed at assessing the expression of HLA‐G at transcriptional and proteic levels during differentiation and maturation of the different DC subsets. We show that HLA‐G transcription was induced during CD34+‐derived DC differentiation and is associated with a cell‐surface expression in half of cases and with a substantial secretion of soluble HLA‐G in all cases. Results were very similar for monocyte‐derived DC, but there was still a weak HLA‐G cell‐surface expression and a lower level of secretion. On the contrary, HLA‐G transcription was weak in plasmacytoid DC without any HLA‐G cell‐surface expression and with a basal level of secretion. The mechanisms involved in HLA‐G expression appear transcriptional and post‐transcriptional. However, the amount of HLA‐G transcripts and the expression of the protein are not related. HLA‐G expression or secretion by DC may have negative consequences on the function of effective immune cells and also on DC themselves via the interaction with inhibitory receptors expressed by these cells. The capacity of DC to express or secrete HLA‐G should be studied in the context of cellular therapy using DC in addition to its suppressive action in immune response.
Human Vγ9Vδ2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. ...They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying Vγ9Vδ2 T-cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in γδ T-cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule-1 (DNAM-1) and CD96 were expressed by Vγ9Vδ2 T cells. The ligands Nectin-like-5 specific of both DNAM-1 and CD96, and also Nectin-2, an additional ligand of DNAM-1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb-mediated masking experiments that cytotoxicity against HCC cells as well as IFN-γ production in γδ T cells were dependent on DNAM-1. Our experiments indicated that Nectin-like-5 but not Nectin-2 was involved in DNAM-1-dependent γδ T-cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC.
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