Casimir de Rham

Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion

Microenvironment molecular cues direct T helper (Th) cell differentiation; however, Th17 fate determination is still imprecisely understood in humans. To assess the role of prostaglandin E(2) (PGE(2)) in Th expansion, we activated peripheral blood mononuclear cells by CD3 cross-linking. In the presence of exogenous PGE(2), peripheral blood mononuclear cells produced higher interleukin-17 (IL-17), C-C chemokine ligand 20 (CCL20)/macrophage inflammatory protein 3alpha (MIP-3alpha), CXC chemokine ligand 8 (CXCL8)/IL-8, and lower interferon-gamma and IL-22 levels than in control cultures. Exogenous PGE(2) and IL-23 synergized in inducing IL-17, whereas indomethacin and IL-23 blockade drastically reduced IL-17 but not interferon-gamma production. Furthermore, IL-1 but not tumor necrosis factor was absolutely required for IL-17 production. PGE(2) doubled the frequency of CD4+ T cells producing IL-17 and within the CD4+ subset enhanced C-C chemokine receptor 6 (CCR6) and CCR4 while decreasing CXC chemokine receptor 3 (CXCR3) expression. Furthermore, in CD4+ T-cell lines, the production of IL-17 segregated with the CCR6+ subset. In the presence of CCR6+ compared with CXCR3+ Th cells, monocytes/macrophages produced much higher levels of matrix metalloproteinase-1, -3, and -9 but similar levels of CXCL10 and IL-1beta. These results identify PGE(2) and IL-23 as participating in the expansion of CD4+ T cells endowed with high IL-17 production capacity, which in turn favors monocyte production of mediators important for host defense and tissue destruction.

The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors

Natural killer (NK) cells play a crucial role in the immune response to micro-organisms and tumours. Recent evidence suggests that NK cells also regulate the adaptive T-cell response and that it might be possible to exploit this ability to eliminate autoreactive T cells in autoimmune disease and alloreactive T cells in transplantation. Mature NK cells consist of a highly diverse population of cells that expresses different receptors to facilitate recognition of diseased cells and possibly pathogens themselves. Ex vivo culture of NK cells with cytokines such as IL-2 and IL-15 is an approach that permits significant expansion of the NK cell subpopulations, which are likely to have potent antitumour, antiviral, or immunomodulatory effects in autoimmunity. Our data indicate that the addition of IL-21 has a synergistic effect by increasing the numbers of NK cells on a large scale. IL-2 and IL-15 may induce the expression of killer cell immunoglobulin-like receptors (KIRs) in KIR-negative populations, the c-lectin receptor NKG2D and the natural cytotoxic receptor NKp44. The addition of IL-21 to IL-15 or IL-2 can modify the pattern of the KIR receptors and inhibit NKp44 expression by reducing the expression of the adaptor DAP-12. IL-21 also preserved the production of interferon-γ and enhanced the cytotoxic properties of NK cells. Our findings indicate that the proinflammatory cytokines IL-2, IL-15 and IL-21 can modify the peripheral repertoire of NK cells. These properties may be used to endow subpopulations of NK cells with specific phenotypes, which may be used in ex vivo cellular immunotherapy strategies.

Neural progenitors derived from human embryonic stem cells are targeted by allogeneic T and natural killer cells.

Neural progenitor cells (NPC) of foetal origin or derived from human embryonic stem cells (HESC) have the potential to differentiate into mature neurons after transplantation into the central nervous system, opening the possibility of cell therapy for neurodegenerative disorders. In most cases, the transplanted NPC are genetically unrelated to the recipient, leading to potential rejection of the transplanted cells. Very few data provide reliable information as to the potential immune response of allogeneic neural progenitors derived from HESC. In this study, we analyzed in vitro the allogeneic immune response of T lymphocytes and natural killer (NK) cells to NPC derived from HESC or of foetal origin. We demonstrate that NPC induce T‐cell stimulation and a strong NK cytotoxic response. NK‐cell activity is unrelated to MHC‐I expression but driven by the activating NKG2D receptor. Cyclosporine and dexamethasone previously used in clinical studies with foetal NPC did not only fail to prevent NK alloreactivity but strongly inhibited the terminal maturation from NPC into mature neurons. We conclude that allogenic transplantation of NPC in the central nervous system will most likely require an immunosuppressive regimen targeting allogenic T and NK cells, whereas possible interference with the differentiation of NPC needs to be carefully evaluated.

Activating CD94:NKG2C and inhibitory CD94:NKG2A receptors are expressed by distinct subsets of committed CD8+ TCR αβ lymphocytes

A subset of CD8+ T cells express the natural killer cell receptors CD94:NKG2A or CD94:NKG2C. We found that although many CD8+ T cells transcribe CD94 and NKG2C, expression of a functional CD94:NKG2C receptor is restricted to highly differentiated effector cells. CD94:NKG2A is expressed by a different subset consisting of CCR7+ memory cells and CCR7– effector cells. Since NKG2A can only be induced on naive CD8+ T cells while CD94– memory cells are refractory, it is likely that commitment to the CD94:NKG2A+ subset occurs during the first encounter with antigen. CCR7+CD94:NKG2A+ T cells recirculate through lymph nodes where upon activation, they produce large quantities of IFN‐γ. These cells occur as a separate CD94:NKG2A+ T cell lineage with a distinct TCR repertoire that differs from that of the other CD8+CD94– T cells activated in situ.

Potential and Limitation of HLA-Based Banking of Human Pluripotent Stem Cells for Cell Therapy

Great hopes have been placed on human pluripotent stem (hPS) cells for therapy. Tissues or organs derived from hPS cells could be the best solution to cure many different human diseases, especially those who do not respond to standard medication or drugs, such as neurodegenerative diseases, heart failure, or diabetes. The origin of hPS is critical and the idea of creating a bank of well-characterized hPS cells has emerged, like the one that already exists for cord blood. However, the main obstacle in transplantation is the rejection of tissues or organ by the receiver, due to the three main immunological barriers: the human leukocyte antigen (HLA), the ABO blood group, and minor antigens. The problem could be circumvented by using autologous stem cells, like induced pluripotent stem (iPS) cells, derived directly from the patient. But iPS cells have limitations, especially regarding the disease of the recipient and possible difficulties to handle or prepare autologous iPS cells. Finally, reaching standards of good clinical or manufacturing practices could be challenging. That is why well-characterized and universal hPS cells could be a better solution. In this review, we will discuss the interest and the feasibility to establish hPS cells bank, as well as some economics and ethical issues.

Expression of inhibitory KIR is confined to CD8+ effector T cells and limits their proliferative capacity

A subset of effector/memory CD8+ T cells expresses natural killer cell receptors (NKR). Expression of inhibitory NKR at that stage of T cell differentiation is poorly understood. Interestingly, recent studies in mice indicated that transgenic expression of an inhibitory NKR induced the accumulation of memory T cells by inhibiting activation‐induced cell death (AICD). To further understand the role of inhibitory NKR on T cells, we characterized the subset of human peripheral T cells expressing the inhibitory NKR, CD158b, and studied the modulation of antigen‐driven T cell expansion by an endogenous inhibitory NKR. We found that CD158b expression was confined to a population of CD8+TCRαβ+ effector T cells as defined by a CD45RA+CCR7– phenotype and high constitutive expression of granzyme B1. Few cells expressed the activating form CD158j in the absence of CD158b. Functionally, engagement of CD158b by MHC ligands diminished early TCR signaling, as well as AICD. However, the reduced AICD did not rescue cells for proliferation, since T cell expansion in the presence of CD158b triggering was impaired. Expression of inhibitory NKR on effector CD8+ T cells may explain in part the poor replicative capacity of T cells at that stage of differentiation.

Natural killer cell receptor—Repertoire and functions after induction therapy by polyclonal rabbit anti-thymocyte globulin in unsensitized kidney transplant recipients

Polyclonal rabbit anti-thymocyte globulin (rATG) is widely used in solid organ transplantation (SOT) as induction therapy or to treat corticosteroid-resistant rejection. In vivo, the effect of rATG on natural killer (NK) cells has not been studied. These cells are of particular relevance after SOT because classical immunosuppressive drugs do not inhibit or even can activate NK cells. A cohort of 20 recipients at low immunological risk, that had been receiving rATG as induction therapy, was analyzed for receptor repertoire, cytotoxicity and capacity of NK cells to secrete IFN-γ before kidney transplantation and at different time points thereafter. NK cells expressed fewer killer-cell immunoglobulin-like receptors (KIR), fewer activating receptors NKG2D, but more inhibitory receptor NKG2A compatible with an immature phenotype in the first 6 months post transplantation. Both cytotoxicity of NK cells and the secretion of IFN-γ were preserved over time after transplantation.

How to cross immunogenetic hurdles to human embryonic stem cell transplantation

Implantation of human embryonic stem cells (hES), derived progenitors or mature cells derived from hES has great therapeutic potential for many diseases. If hES would come from genetically unrelated individuals, it would be probably rejected by the immune system of the recipient. Blood groups, MHC and minor antigens are the immunogenetic hurdles that have to be crossed for successful transplantation. Autologous transplantation with adult stem cells would be the best approach but several elements argue against this option. Classical immunosuppression, depleting antibody, induction of tolerance and stem cell banking are alternative methods that could be proposed to limit the risk of rejection.

Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation

Human cytomegalovirus (CMV) infection may be a serious complication related to immunosuppression after solid organ transplantation. Due to their cytotoxicity, T-cells and natural killer (NK) cells target and clear the virus from CMV-infected cells. Although immunosuppressive drugs suppress T-cell proliferation and activation, they do not affect NK cells that are crucial for controlling the infection. The regulation of NK cells depends on a wide range of activating and inhibitory receptors such as the family of killer-cell immunoglobulin-like receptors (KIRs). Several human genetic studies have demonstrated the association of KIR genes with the clearance of infections. Since the respective activities of the different KIR proteins expressed by NK cells during CMV infection have not been extensively studied, we analyzed the expression of KIRs in a cohort of 22 CMV-IgG(+) renal transplant patients at the time of CMV reactivation, after antiviral therapy and 6 months later. Our data revealed a marked expression of KIR3DL1 during the acute phase of the reactivation. We set up an in vitro model in which NK cells, derived either from healthy donors or from transplanted patients, target allogeneic fibroblasts, CMV-infected or uninfected. Our results demonstrate a significant correlation between the lysis of CMV-infected fibroblasts and the expression of KIR3DL1. Blocking experiments with antibodies to MHC-I, to NKG2D and to NKG2C confirmed the importance of KIR3DL1. Consequently, our results suggest that KIR proteins and especially KIR3DL1 could play an important role during CMV-infection or CMV reactivation in immunosuppressed patients.

A significant effect of the killer cell immunoglobulin-like receptor ligand human leucocyte antigen-C on fibrosis progression in chronic C hepatitis with or without liver transplantation.

The interaction of killer cell immunoglobulin–like receptors with their human leucocyte antigen ligands drives the activation and inhibition of natural killer cells. Natural killer cells could be implicated in the development of liver fibrosis in chronic hepatitis C.