CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo

Two distinct populations of Bovine IL-17+ T-cells can be induced and WC1+IL-17+γδ T-cells are effective killers of protozoan parasites

IL-17 has emerged as a key player in the immune system, exhibiting roles in protection from infectious diseases and promoting inflammation in autoimmunity. Initially thought to be CD4 T-cell-derived, the sources of IL-17 are now known to be varied and belong to both the innate and adaptive arms of the immune system. Mechanisms for inducing IL-17 production in lymphoid cells are thought to rely on appropriate antigenic stimulation in the context of TGF-β1, IL-6 and/or IL-1β. Using culture protocols adapted from human studies, we have effectively induced both bovine CD4+ and WC1+ γδ T-cells to produce IL-17 termed Th17 and γδ17 cells, respectively. The negative regulatory effect of IFN-γ on mouse and human IL-17 production can be extended to the bovine model, as addition of IFN-γ decreases IL-17 production in both cell types. Furthermore we show that infection with the protozoan Neospora caninum will induce fibroblasts to secrete pro-IL-17 factors thereby inducing a γδ17 phenotype that preferentially kills infected target cells. Our study identifies two T-cell sources of IL-17, and is the first to demonstrate a protective effect of IL-17+ T-cells in ruminants. Our findings offer further opportunities for future adjuvants or vaccines which could benefit from inducing these responses

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

IFN-γ– and IL-10–expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis

Pathogen-specific Foxp3+ T reg cells can be identified on the basis of cytokine production, are detected in naive T cell populations, and exhibit suppressive ability toward effector T cells with the same antigen specificity

Immunization with Toxoplasma gondii GRA17 deletion mutant induces partial protection and survival in challenged mice

Toxoplasmosis remains a world-threatening disease largely because of the lack of a fully effective vaccine. Here, we created a ΔGRA17 mutant by disrupting the virulence factor GRA17 using CRISPR-Cas9 method. Then, we tested whether ΔGRA17 tachyzoites can be used as a live-attenuated vaccine against acute, chronic, and congenital Toxoplasma gondii infection in mice. Immune response evoked by ΔGRA17 immunization suggested a sequential Th1 and Th2 T cell response, indicated by high levels of Th1 and a mixed Th1/Th2 cytokines at 28 and 70 days after immunization, respectively. ΔGRA17-mediated immunity fully protected mice against lethal infection with wild-type (wt) RH strain, heterologous challenge with PYS, and TgC7 strains of the Chinese ToxoDB#9 genotype, and T. gondii Pru strain. Although parasite cysts were detected in 8 out of 10 immunized mice, cyst burden in the brain was significantly reduced (P < 0.05) in immunized mice (53 ± 15 cysts/brain) compared to non-immunized mice (4,296 ± 687 cysts/brain). In respect to congenital infection, the litter size, survival rate, and body weight (BW) of pups born to ΔGRA17-immunized dams were not different compared to pups born to naïve control dams (P = 0.24). However, a marked reduction in the litter size (P < 0.001), survival rate, and BW (P < 0.01) of pups born to non-immunized and infected dams was detected. Also, immunized dams infected with type II Pru strain had significantly (P < 0.001) less cyst burden in the brain compared with non-immunized and infected dams. These findings show that immunization with ΔGRA17 strain evokes cell-mediated and neutralizing antibody responses and confers some degree of protection against challenge with homologous and heterologous virulent T. gondii strains

Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice

Regulatory T cells generated by allostimulation with dendritic cells, transforming growth factor β, and retinoic acid stably express Foxp3 and can suppress even ongoing GVHD in mice

Thymus‐derived regulatory T cells restrain pro‐inflammatory Th1 responses by downregulating CD

The severity and intensity of autoimmune disease in Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasizes the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4+ T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responsesin pressSCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns

T-bet acts as a functional repressor in association with Bcl-6 to antagonize SOCS1, SOCS3, TCF-1, and late-stage IFN-γ to regulate Th1 development

SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells