Renneson J, Dutta B, Goriely S, Danis B, Lecomte S, Laes J.F, Tabi Z, Goldman M, Marchant A. IL-12 and type I IFN response of neonatal myeloid DC to human CMV infection. Eur J Immunol 2009; 39:2789-2799.

Following congenital human CMV (HCMV) infection, 15-20% of infected newborns develop severe health problems whereas infection in immunocompetent adults rarely causes illness. The immaturity of neonatal antigen presenting cells could play a pivotal role in this susceptibility. Neonatal myeloid DC were shown to be deficient in IFN-b and IL-12 synthesis in response to TLR triggering. We studied the response of cord and adult bloodderived myeloid DC to HCMV infection. Neonatal and adult DC were equally susceptible to in vitro HCMV infection. Among immunomodulatory cytokines, IL-12, IFN-b and IFN-k1 were produced at lower levels by neonatal as compared with adult DC. In contrast, neonatal and adult DC produced similar levels of IFN-a and IFN-inducible genes. Microarray analysis indicated that among the more than thousand genes up- or down-regulated by HCMV infection of myeloid DC, 88 were differently regulated between adult and neonatal DC.We conclude that neonatal and adult DC trigger a partly different response to HCMV infection. The deficient IL-12 and mature IFN-a production by neonatal DC exposed to HCMV are likely to influence the quality of the T lymphocyte response to HCMV infection in early life.

Ravoet M, Sibille C, Gu C, Libin M, Haibe Kains B, Sotiriou C, Goldman M, Roufosse F, Willard Gallo K. Molecular profiling of CD3-CD4+ tycells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways. Blood 2009; 114:2969-2983.

The clonal CD3-CD4 T-cell population characterizing lymphocytic variant hypereosinophilic syndrome (L-HES) persists for years, with a subgroup of patients ultimately progressing to T lymphoma. The molecular changes associated with the premalignant clone and the emergence of malignant subclones are unknown, precluding the development of targeted therapy for this HES variant. In this study, we used whole genome arrays to examine gene expression in the CD3 CD4 T cells and found that 850 genes were differentially regulated during chronic disease compared with CD3 CD4 T cells from healthy donors. Changes in the expression of 349 genes were altered in association with the clinical progression from chronic L-HES to T lymphoma in 1 patient, with 87 of 349 genes representing further changes in genes whose expression was altered in all chronic disease patients (87 of 850). Array analysis after CD2/CD28-mediated activation revealed that the major gene expression changes observed in the CD3-CD4 T cells do not reflect activation induced alterations but rather pathways involved in T-cell homeostasis, including transforming growth factor-bsignaling, apoptosis, and T-cell maturation, signaling, and migration. Examination of micro RNA expressioning the CD3 CD4 T cells from patients with chronic disease identified 23 micro-RNAs that changed significantly, among which miR-125a further decreased in association with one patient's evolution to T lymphoma.

Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, Gaudray F, Goldman M, Salmon I, Braun M. Reviving function in CD4+ T cells adapted to persistent systemic antigen. J Immunol 2009; 183:4284-4291.

In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient's mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo. However, analysis of the gene expression profile of adapted CD4⁺ T cells revealed the specific coexpression of genes known to promote  differentiation and function of Th1 effector cells as well as genes coding for proteins that control T cell activity, such as cell surface-negative costimulatory molecules and regulatory cytokines. Strikingly, blockade of negative costimulation abolished T cell adaptation and stimulated strong IFN-γ production and severe multiorgan wasting disease. Negative costimulation was also shown to control lethal LPS-induced toxic shock in mice with adapted T cells, as well as the capacity of adapted T cells to reject skin graft. Our results demonstrate that negative costimulation is the molecular mechanism used by CD4⁺ T cells to adapt their activity in response to persistent antigenic stimulation. The effector function of CD4⁺ T cells that have adapted to chronic Ag presentation can be activated by stimuli strong enough to overcome regulatory signals delivered to the T cells by negative costimulation.

De Wilde V, Van Rompaey N, Hill M, Lebrun J.F, Lemaître P, Lhommé F, Kubjak C, Vokaer B, Oldenhove G, Charbonnier L.M, Cuturi M.C, Goldman M, Le Moine A Endotoxin-induced myeloid-derived suppressor cell inhibits alloimmune responses via oxygenase-1. Am J Transplant 2009; 9:1-14.

Inflammation and cancer are associated with impairment of T-cell responses by a heterogeneous population of myeloid-derived suppressor cells (MDSCs) coexpressing CD11b and GR-1 antigens. MDSCs have been recently implicated in costimulation blockade-induced transplantation tolerance in rats, which was under the control of inducible NO synthase (iNOS). Herein, we describe CD11b+GR-1+MDSC-compatible cells appearing after repetitive injections of lipopolysaccharide (LPS) using a unique mechanism of suppression. These cells suppressed T-cell proliferation and Th1 and Th2 cytokine production in both mixed lymphocyte reaction and polyclonal stimulation assays. Transfer of CD11b+ cells from LPS-treated mice in untreated recipients significantly prolonged skin allograft survival. They produced large amounts of IL-10 and expressed heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with immunoregulatory and cytoprotective properties not previously associated with MDSC activity. HO-1 inhibition by the specific inhibitor, SnPP, completely abolished T-cell suppression and IL-10 production. In contrast, neither iNOS nor arginase 1 inhibition did affect suppression. Importantly, HO-1 inhibition before CD11b+ cell transfer prevented the delay of allograft rejection revealing a new MDSC-associated suppressor mechanism relevant for transplantation.

Goldman M, Wood K. Transplating transplantation tolerance in the clinic: where are we, where do we go? Clin Exp Immunol 2009; 156:185-188.

Transplantation tolerance is defined as the permanent acceptance of a grafted organ in absence of immunosuppression.  This state of tolerance is considered as the Holy Grail by transplant scientists.  Recent advances in our understanding of tolerance in animal models led to launch pilot clinical trials aiming at the withdrawal of immunosuppressive drugs in transplant recipients. Furthermore, research networks were built in USA (Immune Tolerance Network) and in Europe (The RISET integrated project coordinated by IMI) for this purpose.  Herein, we discuss the major lessons learned so far and we review the multiples hurdles to transplantation tolerance in humans.  On this basis, we propose that the next major advances in the field of transplantation might depend on tailoring immunosuppression according to biomarkers.

Willems F,Vollstedt S and Suter M Phenotype and function of neonatal DC
Eur. J. Immunol. 2009; 39:26-35.

Newborns face complex physical and immunological changes before and after birth. Although the uterus is a sterile environment for the fetus, it also contains non-self material from the mother. Birth involves the transition from the sterile intra-uterine environment to an environment rich in microbes and requires rapid induction of appropriate responses to control these microbes. In this review we focus on the similarities and differences of human andmurine neonatal DC and their reaction to various stimuli. A better understanding of the newborn immune system- in particular, the DC-T-cell interaction - will be beneficial for the development of improved strategies to prevent or treat infections in this vulnerable population and prepare the immune system to cope with allergens and tumors later in life.

Benghiat FS, Charbonnier LM, Vokaer B, De Wilde V, Le Moine A. Interleukin 17-producing T helper cells in alloimmunity. Transplant Rev 2009; 23:11-18.

Interleukin (IL) 17 is a proinflammatory cytokine already known to play a defense role against microbes and a pathogenic role in a number of autoimmune diseases. Although IL-17 can be produced by a variety of cells including neutrophils, CD8+, NK, and gamma-delta T cells, the concept of IL-17-secreting CD4+ T helper cells (Th17), distinct from Th1 and Th2, recently emerged. This study discuss arguments in favor of a Th17-mediated alternative pathway of allograft rejection based on clinical and experimental observations drawn from the literature. It also discuss the complex interplays among regulatory T cells and Th17 cells in the allogeneic context.