Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic... Show moreType 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4(+) T cells may offer a tissue-specific intervention therapy. The effect of Combi-DCs on CD8(+) T cells, however, remains unknown. To investigate the interaction of CD8(+) T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8(+) T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naïve CD8(+) T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8(+) T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8(+) T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8(+) T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8(+) T-cell immunity. Yet, Combi-DCs pulsed with CD8(+) T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies. Show less
Zehner, M.; Rauen, J.; Chasan, A.I.; Embgenbroich, M.; Camps, M.G.; Kaden, S.; ... ; Burgdorf, S. 2012
Mounting evidence indicates that the cytokine IL-21 can significantly enhance the survival of CD8(+) T lymphocytes. Given that CD4(+) T lymphocytes constitute the main cellular source for IL-21 in... Show moreMounting evidence indicates that the cytokine IL-21 can significantly enhance the survival of CD8(+) T lymphocytes. Given that CD4(+) T lymphocytes constitute the main cellular source for IL-21 in vivo, it is tempting to speculate a direct role in mediating the "help" provided by these CD4(+) T cells to the CD8 response. A new report in this issue of the European Journal of Immunology advances this notion by showing that CD8(+) T cells lacking the IL-21 receptor phenocopy those primed in the absence of CD4(+) T cells (the so-called "helpless" CD8(+) T cells) in their induction of the pro-apoptotic factor TRAIL. This finding helps to define the role of IL-21 in the CD8 response, and raises new questions relevant for achieving a broader understanding of this multifunctional cytokine. Show less
Mounting evidence indicates that the cytokine IL-21 can significantly enhance the survival of CD8(+) T lymphocytes. Given that CD4(+) T lymphocytes constitute the main cellular source for IL-21 in... Show moreMounting evidence indicates that the cytokine IL-21 can significantly enhance the survival of CD8(+) T lymphocytes. Given that CD4(+) T lymphocytes constitute the main cellular source for IL-21 in vivo, it is tempting to speculate a direct role in mediating the "help" provided by these CD4(+) T cells to the CD8 response. A new report in this issue of the European Journal of Immunology advances this notion by showing that CD8(+) T cells lacking the IL-21 receptor phenocopy those primed in the absence of CD4(+) T cells (the so-called "helpless" CD8(+) T cells) in their induction of the pro-apoptotic factor TRAIL. This finding helps to define the role of IL-21 in the CD8 response, and raises new questions relevant for achieving a broader understanding of this multifunctional cytokine. Show less
Piersma, S.J.; Hulst, J.M. van der; Kwappenberg, K.M.C.; Goedemans, R.; Minne, C.E. van der; Burg, S.H. van der 2010
Control and termination of infection with Influenza A virus is associated with increased IL-10 production in mouse models. Notably, IL-10 can be produced by Treg. Therefore, we investigated whether... Show moreControl and termination of infection with Influenza A virus is associated with increased IL-10 production in mouse models. Notably, IL-10 can be produced by Treg. Therefore, we investigated whether the population of IL-10-producing influenza-specific CD4(+) T cells comprised Treg as they are potent suppressors of the adaptive immune response. Influenza-specific IL-10-producing T cells were detected in all human donors displaying influenza-specific immunity. Isolation of Matrix 1 protein-specific IL-10-producing T-cell clones revealed that a substantial proportion of these T-cell clones displayed the capacity to suppress effector cells, functionally identifying them as Treg. Both FOXP3(+) and FOXP3(-) CD4(+) Treg were isolated and all were able to exert their suppressive capacity when stimulated with cognate antigen, including influenza virus-infected cells. In vitro suppression was not mediated by IL-10 but involved interference with the IL-2 axis. The isolated Treg suppressed amongst others the IL-2 production of influenza-specific T-helper cells as well as partially prevented the upregulation of the high-affinity IL-2 receptor on CD8 effector cells. So far the induction of virus-specific Treg has only been studied in the context of chronic viral infections. This study demonstrates that virus-specific Treg can also be induced by viruses that are rapidly cleared in humans. Show less
Han, W.G.H.; Voort, E.I.H. van der; Bannoudi, H. el; Louis-Plence, P.; Huizinga, T.W.J.; Toes, R.E.M. 2010
CD4(+) Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune... Show moreCD4(+) Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune-modulatory properties are beneficial for inhibiting such inflammatory responses. Previously we demonstrated that repetitive injections of immature DC induce expansion of DX5(+)CD4(+) T cells, which upon adoptive transfer show potent regulatory properties in murine collagen-induced arthritis as well as in delayed-hypersensitivity models. However, their regulatory mechanism remains to be defined. Here, we analyzed the effect of DX5(+)CD4(+) T cells on other CD4(+) T cells in vitro. Although proliferation of naive CD4(+) T cells upon antigenic triggering was not altered in the presence of DX5(+)CD4(+) T cells, there was a striking difference in cytokine production. In the presence of DX5(+)CD4(+) T cells, an IL-10-producing CD4(+) T-cell response was induced instead of a predominant IFN-gamma-producing Th1 response. This modulation did not require cell-cell contact. Instead, IL-4 produced by DX5(+)CD4(+) T cells was primarily involved in the inhibition of IFN-gamma and promotion of IL-10 production by CD4(+) T cells. Together, our data indicate that DX5(+)CD4(+) T cells modulate the outcome of Th-responses by diverting Th1-induction into Th responses characterized by the production of IL-10. Show less
Han, W.G.H.; Voort, E.I.H. van der; Bannoudi, H. el; Louis-Plence, P.; Huizinga, T.W.J.; Toes, R.E.M. 2010
CD4(+) Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune... Show moreCD4(+) Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune-modulatory properties are beneficial for inhibiting such inflammatory responses. Previously we demonstrated that repetitive injections of immature DC induce expansion of DX5(+)CD4(+) T cells, which upon adoptive transfer show potent regulatory properties in murine collagen-induced arthritis as well as in delayed-hypersensitivity models. However, their regulatory mechanism remains to be defined. Here, we analyzed the effect of DX5(+)CD4(+) T cells on other CD4(+) T cells in vitro. Although proliferation of naïve CD4(+) T cells upon antigenic triggering was not altered in the presence of DX5(+)CD4(+) T cells, there was a striking difference in cytokine production. In the presence of DX5(+)CD4(+) T cells, an IL-10-producing CD4(+) T-cell response was induced instead of a predominant IFN-γ-producing Th1 response. This modulation did not require cell-cell contact. Instead, IL-4 produced by DX5(+)CD4(+) T cells was primarily involved in the inhibition of IFN-γ and promotion of IL-10 production by CD4(+) T cells. Together, our data indicate that DX5(+)CD4(+) T cells modulate the outcome of Th-responses by diverting Th1-induction into Th responses characterized by the production of IL-10. Show less
Caccamo, N.; Guggino, G.; Joosten, S.A.; Gelsomino, G.; Carlo, P. di; Titone, L.; ... ; Dieli, F. 2010
Th1 CD4(+) T cells and their derived cytokines are crucial for protection against Mycobacterium tuberculosis. Using multiparametic flow cytometry, we have evaluated the distribution of seven... Show moreTh1 CD4(+) T cells and their derived cytokines are crucial for protection against Mycobacterium tuberculosis. Using multiparametic flow cytometry, we have evaluated the distribution of seven distinct functional states (IFN-gamma/IL-2/TNF-alpha triple expressors, IFN-gamma/IL-2, IFN-gamma/TNF-alpha or TNF-alpha/IL-2 double expressors or IFN-gamma, IL-2 or TNF-alpha single expressors) of CD4(+) T cells in individuals with latent M. tuberculosis infection (LTBI) and active tuberculosis (TB). We found that triple expressors, while detectable in 85-90%TB patients, were only present in 10-15% of LTBI subjects. On the contrary, LTBI subjects had significantly higher (12- to 15-fold) proportions of IL-2/IFN-gamma double and IFN-gamma single expressors as compared with the other CD4(+) T-cell subsets. Proportions of the other double or single CD4(+) T-cell expressors did not differ between TB and LTBI subjects. These distinct IFN-gamma, IL-2 and TNF-alpha profiles of M. tuberculosis-specific CD4(+) T cells seem to be associated with live bacterial loads, as indicated by the decrease in frequency of multifunctional T cells in TB-infected patients after completion of anti-mycobacterial therapy. Our results suggest that phenotypic and functional signatures of CD4(+) T cells may serve as immunological correlates of protection and curative host responses, and be a useful tool to monitor the efficacy of anti-mycobacterial therapy. Show less
Rosario, M.; Bridgeman, A.; Quakkelaar, E.D.; Quigley, M.F.; Hill, B.J.; Knudsen, M.L.; ... ; Hanke, T. 2010
A novel T-cell vaccine strategy designed to deal with the enormity of HIV-1 variation is described and tested for the first time in macaques to inform and complement approaching clinical trials. T... Show moreA novel T-cell vaccine strategy designed to deal with the enormity of HIV-1 variation is described and tested for the first time in macaques to inform and complement approaching clinical trials. T-cell immunogen HIVconsv, which directs vaccine-induced responses to the most conserved regions of the HIV-1, proteome and thus both targets diverse clades in the population and reduces the chance of escape in infected individuals, was delivered using six different vaccine modalities: plasmid DNA (D), attenuated human (A) and chimpanzee (C) adenoviruses, modified vaccinia virus Ankara (M), synthetic long peptides, and Semliki Forest virus replicons. We confirmed that the initial DDDAM regimen, which mimics one of the clinical schedules (DDDCM), is highly immunogenic in macaques. Furthermore, adjuvanted synthetic long peptides divided into sub-pools and delivered into anatomically separate sites induced T-cell responses that were markedly broader than those elicited by traditional single-open-reading-frame genetic vaccines and increased by 30% the overall response magnitude compared with DDDAM. Thus, by improving both the HIV-1-derived immunogen and vector regimen/delivery, this approach could induce stronger, broader, and theoretically more protective T-cell responses than vaccines previously used in humans. Show less
Everts, B.; Smits, H.H.; Hokke, C.H.; Yazdanbakhsh, M. 2010
The classical reaction of the host to helminth infections is the induction of Th2 immune responses with a regulatory component. DC, as central players in the induction and maintenance of immune... Show moreThe classical reaction of the host to helminth infections is the induction of Th2 immune responses with a regulatory component. DC, as central players in the induction and maintenance of immune responses, play a prominent role in both these processes, and in recent years considerable progress has been made in elucidating the mechanisms behind the interplay between DC and helminths. It is becoming increasingly clear that helminths modulate DC function not only via direct interactions but also indirectly via host-derived cues. Furthermore, while studies have until recently focused on receptor signaling-mediated DC modulation by helminths, evidence is emerging that DC may also respond to helminth infections by sensing stress signals or tissue damage inflicted by the worms or their products. Here, we will discuss these new insights and will link them to the origin and importance of Th2 and regulatory immune responses with respect to the survival of both parasite and host. Show less
Wammes, L.J.; Hamid, F.; Wiria, A.E.; Gier, B. de; Sartono, E.; Maizels, R.M.; ... ; Yazdanbakhsh, M. 2010
Chronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on... Show moreChronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum-parasitized RBC in Indonesian schoolchildren. Geohelminth-infected children's in vitro T-cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD4(+)CD25(hi)FOXP(3+) T cells was similar regardless of infection status, the suppressive activity differed between geohelminth-infected and geohelminth-uninfected groups: Ag-specific proliferative responses increased upon CD4(+)CD25(hi) T-cell depletion in geohelminth-infected subjects only. in addition, IFN-gamma production in response to both BCG and parasitized RBC was increased after removal of CD4(+)CD25(hi) T cells. These data demonstrate that geohelminth-associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth-induced immune modulation may have important consequences for co-endemic infections and vaccine trials. Show less
