Final Activity Report Summary - DCGDNKNEO (Interaction between human dendritic cells and gamma delta T cells/NK cells in neonates)
It has been previously shown that dendritic cells from human new-borns have a lower capacity than their adult counterparts to activate helper T lymphocytes. There is now ample evidence that gammadelta T lymphocytes and NK cells exert important regulatory actions on dendritic cells which in turn deliver activating signals to these innate lymphocytes. This crosstalk influences adaptive immune responses dependent on helper T cells. We propose to evaluate the bidirectional interactions between dendritic cells - of the myeloid or lymphoid lineages - and gammadelta T cells or NK cells in human new-borns. The influence of Toll-like receptor ligands, phosphoantigens and Bacille Calmette-Guerin will be assessed using in vitro models.
In parallel, we are taking advantage of clinical samples obtained from newborns congenitally infected with cytomegalovirus (collaboration with Arnaud Marchant at the IMI-ULB) to assess the function of gammadelta T cells and NK cells upon exposure to this virus during fetal life. The fetus and infant are highly susceptible to viral infections. A number of viruses, including human cytomegalovirus (HCMV), cause severe disease in early life compared to later life. It is generally accepted that this higher susceptibility to viral infections is due to the immaturity of the immune system. Gammadelta T cells are unconventional lymphocytes that can react rapidly upon activation and show MHC-unrestricted activity; thus, they are not influenced by viral immune evasion strategies inhibiting MHC class I expression. In adult, human gammadelta T cells have been shown to react towards HCMV infection in settings of immunosuppression, but their role in viral infection in fetal life has not been addressed before.
To explore the role of human gammadelta T cells in neonatal dendritic cells maturation, experiments were performed using the most potent phosphoantigen HMB-PP and the aminobisphosponate zoledronate, a drug that is already used in the clinic. We showed that neonatal gammadelta (Vgamma9+) T cells can be specifically activated (proliferation, IFNgamma) via zoledronate. This will be further investigated in detail in order to establish the optimal experimental conditions to analyse the interactions between activated neonatal gammadelta T cells and dendritic cells.
In non-infected new-borns, we confirmed that the majority of gammadelta T cells showed a naïve phenotype. In contrast, HCMV infection in utero resulted in a clear differentiation and activation of gammadelta T cells. In particular, a large part of the gammadelta T cells of new-borns showed a late differentiated phenotype (CD27-CD28-CD45RA+) which was accompanied by high expression levels of the effector molecules perforin and granzyme A and of the activation marker HLA-DR. We could detect similar changes as early as after 22 weeks of gestation. In addition, we showed that upon CMV infection, the Vdelta1 chain shows a restricted repertoire. The observation of mature gammadelta T cell reactivity to HCMV both at foetal and neonatal stages suggests a critical role for this cell type in the cellular immune defence against an acute HCMV infection in early life.
In parallel, we are taking advantage of clinical samples obtained from newborns congenitally infected with cytomegalovirus (collaboration with Arnaud Marchant at the IMI-ULB) to assess the function of gammadelta T cells and NK cells upon exposure to this virus during fetal life. The fetus and infant are highly susceptible to viral infections. A number of viruses, including human cytomegalovirus (HCMV), cause severe disease in early life compared to later life. It is generally accepted that this higher susceptibility to viral infections is due to the immaturity of the immune system. Gammadelta T cells are unconventional lymphocytes that can react rapidly upon activation and show MHC-unrestricted activity; thus, they are not influenced by viral immune evasion strategies inhibiting MHC class I expression. In adult, human gammadelta T cells have been shown to react towards HCMV infection in settings of immunosuppression, but their role in viral infection in fetal life has not been addressed before.
To explore the role of human gammadelta T cells in neonatal dendritic cells maturation, experiments were performed using the most potent phosphoantigen HMB-PP and the aminobisphosponate zoledronate, a drug that is already used in the clinic. We showed that neonatal gammadelta (Vgamma9+) T cells can be specifically activated (proliferation, IFNgamma) via zoledronate. This will be further investigated in detail in order to establish the optimal experimental conditions to analyse the interactions between activated neonatal gammadelta T cells and dendritic cells.
In non-infected new-borns, we confirmed that the majority of gammadelta T cells showed a naïve phenotype. In contrast, HCMV infection in utero resulted in a clear differentiation and activation of gammadelta T cells. In particular, a large part of the gammadelta T cells of new-borns showed a late differentiated phenotype (CD27-CD28-CD45RA+) which was accompanied by high expression levels of the effector molecules perforin and granzyme A and of the activation marker HLA-DR. We could detect similar changes as early as after 22 weeks of gestation. In addition, we showed that upon CMV infection, the Vdelta1 chain shows a restricted repertoire. The observation of mature gammadelta T cell reactivity to HCMV both at foetal and neonatal stages suggests a critical role for this cell type in the cellular immune defence against an acute HCMV infection in early life.