HLA-G inhibits the allogeneic proliferative response

Riteau, Béatrice; Menier, Catherine; Khalil-Daher, Iman; Sedlik, Christine; Dausset, J; Rouas‐Freiss, Nathalie; Carosella, Edgardo D.

doi:10.1016/s0165-0378(99)00034-0

Cited by 165 publications

(129 citation statements)

References 13 publications

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“…In the light of its inhibitory role in T-lymphocyte proliferation, 14 we first investigated the effect of HLA-G5 on normal erythroid cell proliferation. For this purpose, we used UT7/EPO cells, 15 the EPOR signal transduction and proliferation of which are similar to those of erythroid progenitors in response to EPO.…”

Section: Resultsmentioning

confidence: 99%

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

et al. 2007

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HLA-G5 is secreted by erythroblasts in all hematopoietic organs, suggesting a role for this protein in erythropoiesis. To examine this, we analyzed whether HLA-G5 affects the proliferation of UT7/EPO and HEL erythroleukemia cells and characterized the mechanism by which HLA-G5 influences erythropoietin receptor (EPOR) signaling. We show that HLA-G5 inhibits the proliferation of UT7/EPO cells, the EPOR signaling of which is similar to that of normal erythroid progenitors. HLA-G5-mediated inhibition was associated with reduced phosphorylation of JAK2 kinase and that of the downstream signaling proteins STAT-5 and STAT-3. Involvement of JAK2 in erythroid cell proliferation has been highlighted by the role of JAK2 V617F mutation in polycythemia vera (PV), a myeloproliferative disorder characterized by erythroid lineage overproduction. We demonstrate that HLA-G5 downregulates EPOR constitutive signaling of JAK2 V617F-expressing HEL cells, leading to inhibition of cell proliferation through G1 cell cycle arrest. Combination of HLA-G5 with JAK inhibitor I further decreases HEL cell growth. Clinical relevance is provided by analysis of PV patients who carry JAK2 V617F mutation, showing that HLA-G5 inhibits the formation of erythropoietin-independent erythroid colonies. Such HLA-G5-mediated inhibition constitutes a new parameter to be considered in the design of future approaches aimed at treating JAK2 V617F-positive myeloproliferative disorders.

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Section: Resultsmentioning

confidence: 99%

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

et al. 2007

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“…In particular, soluble HLA-G induces apoptosis of CD8 + T and NK cells and may participate in allograft tolerance through peripheral deletion of alloreactive T cells after allotransplantation in vivo [21,22]. Previous analysis of the functional role of both HLA-G1 and HLA-G5 in mixed lymphocyte reaction showed that both suppress the alloproliferative response of T cells [23,24,29]. Such inhibition could be reversed by the use of anti-HLA-G mAb [24].…”

Section: Discussionmentioning

confidence: 99%

“…Since HLA-G inhibits T cell functions [23,24], we analyzed the T cell alloproliferative response of the sixteen allogeneic combinations after 6 days of MLR. Strong proliferative responses were observed for all these allogeneic combinations.…”

Section: Hla-g1 And/or Hla-g5 Expression Is Induced After Mixed Lymphmentioning

confidence: 99%

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Alloreactive CD4⁺ and CD8⁺ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients

et al. 2004

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HLA‐G displays immunotolerogenic properties towards the main effector cells involved in graft rejection through inhibition of NK‐ and CTL‐mediated cytolysis and CD4+ T cell alloproliferation. HLA‐G expression is restricted in healthy tissues to trophoblast and thymus but is extended to various tissues under pathological conditions. HLA‐G was detected in allograft biopsies and sera from transplanted patients who displayed a better graft acceptance. However, the cells involved in such de novo expression of HLA‐G remain to be characterized. By flow cytometry and confocal microscopy, we demonstrated that, following allogeneic stimulation in vitro, both CD4+ and CD8+ T cell subsets can express membrane‐bound HLA‐G1 and/or soluble HLA‐G5molecules. Such HLA‐G1/‐G5 expression is regulated at the transcriptional level. Soluble HLA‐G5 could be detected by using a novel monoclonal antibody, 5A6G7, specific for the intron 4‐retaining sequence of HLA‐G5. Finally, the biological relevance of these data was provided by analysis of transplanted patients in whom we identified both CD4+ and CD8+ T cells expressing HLA‐G. The HLA‐G‐positive T cells we describe here may constitute a cellular source of HLA‐G after allotransplantation and may be involved in the improved graft acceptance which is observed in HLA‐G‐positive transplanted patients.

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“…In particular, these results show that (i) in some heart transplanted patients, HLA-G is detected in the serum as well as in the transplant, this being correlated with better graft acceptance. The expression of HLA-G by transplanted tissue might participate in graft protection as it was also shown that (ii) allogeneic CD4 π T cells secrete soluble HLA-G5 (20), and that (iii) membrane-bound HLA-G1 or soluble HLA-G5 both inhibit CD4 π T cell alloreactivity (20,21). The protective effect of HLA-G was investigated in the context of xenotransplantation as well, and authors showed that (iv) HLA-G1 inhibits xenogeneic NK cell cytolytic and migratory functions in transfection systems (22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

HLA-G in Transplantation: A Relevant Molecule for Inhibition of Graft Rejection?

Rouas‐Freiss

LeMaoult

Moreau

et al. 2003

American Journal of Transplantation

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The human MHC class I molecule HLA-G has long been known as a molecule selectively expressed by cytotrophoblastic cells. By inhibiting the cytolytic function of decidual NK cells, HLA-G protects the HLA-A and -B negative semiallogeneic embryonic tissue against the mother's immune system. In the light of this immunosuppressive function, the role of HLA-G in transplantation was investigated. We will review here recently published data on this topic, showing that expression of HLA-G affects the responsive capacity of the immune system, might directly participate in graft acceptation, and should be taken into account for the monitoring of transplantation patients.

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HLA-G inhibits the allogeneic proliferative response

Cited by 165 publications

References 13 publications

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

Alloreactive CD4⁺ and CD8⁺ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients

HLA-G in Transplantation: A Relevant Molecule for Inhibition of Graft Rejection?

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HLA-G inhibits the allogeneic proliferative response

Cited by 165 publications

References 13 publications

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

Alloreactive CD4+ and CD8+ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients

HLA-G in Transplantation: A Relevant Molecule for Inhibition of Graft Rejection?

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Alloreactive CD4⁺ and CD8⁺ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients