To show you that increased levels T regulatory cells, CD4+CD25+ FoxP3 (Tregs) are not just some abstract concept, but are associated with severe diseases like cancer and chronic infections, I post some snap shots of studies showing an increase of TREGS in various clinical setting.
Quote
We determined the number and functional status of CD4+CD25high regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide.
Treg numbers were significantly higher in 49 patients with metastatic cancer (9•2% of CD4+ T cells) compared to 24 healthy donors (7•1%).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219383
Quote
Compared with healthy controls,
AML patients had a higher proportion of CD4(+)CD25(high) T cells in peripheral blood. These cells were CD45-RA(-), CD69(-), CD45-RO(+), CD95(+), and intercellular CTLA-4(+), and secreted low levels of TNF-alpha and IL-10, but no IL-2, IL-4, IL-5, and IFN-gamma. They inhibited the proliferation and cytokine production (IL-2, IFN-gamma) of CD4(+)CD25(-) T cells, but improved IL-10 production under the co-culture of both subsets with stimulation, thus behaving as T-reg. Notably, CD4(+)CD25(high) T cells in AML patients presented significantly higher apoptosis and proliferation than that of healthy individuals.
http://www.ncbi.nlm.nih.gov/pubmed/16313258
Quote
However,
increased percentages of CD4+CD25+ T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4+CD25+ T cells were found to secrete transforming growth factor-β, consistent with the phenotype of regulatory T cells. .
http://cancerres.aacrjournals.org/content/61/12/4766.long
Quote
An
increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4+ T cell responses, as observed by IFNc release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group. Conclusions/Significance. Collectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen- specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy.
Quote
Foxp3+CD4+CD25+ regulatory T cells are increased in patients with Coxiella burnetii endocarditis The population of CD4+ T cells that expressed both CD25 and Foxp3 was significantly (P < 0.001) increased in patients with Q fever endocarditis compared with controls. Our data suggest that the expansion of Tregs may be critical for the chronic evolution of Q fever.
Quote
Chronic activity of hepatitis B is thought to involve aberrant immune tolerance of unknown mechanism. In this study, we examined the role of CD4+CD25+Foxp3+ regulatory T cells in disease activity and viral clearance in hepatitis B. Patients with chronic active hepatitis B (CAH) and asymptomatic HBV carriers (AsC) exhibited a significantly
high frequency of CD4+CD25+Foxp3+ T cells as opposed to that of controls and resolved HBV infection. These CD4+CD25+ T cells expressed an elevated level of Foxp3 and displayed increased inhibitory activity towards both CD4+CD25− and CD8+ effector cells.
http://intimm.oxfordjournals.org/content/19/2/133.full
Quote
CD4+Foxp3 regulatory T cells mediate Toxoplasma gondii-induced T-cell suppression through an IL-2- related mechanism but independently of IL-10
We show that selective elimination of Treg cells using Foxp3 EGFP mice leads to a full recovery of CD4+ and CD8+ T-cell proliferation. After Treg-cell removal, a reduced production of IL-10 was observed, but IL-2 levels were unchanged. The numbers of IL-10-producing Treg cells also increased during infection, although the in vitro neutralization of this cytokine did not modify T-cell proliferation, suggesting that IL-10 does not mediate the Treg-mediated suppression. However, addition of rIL-2 in vitro fully restored T-cell proliferation from infected animals. Thus, we show that Treg cells mediate the T-cell suppression observed during acute T. gondii infection through an IL-2-dependent mechanism. Our results provide novel insights into the regulation of the immune response against T. gondii.
Quote
A number of studies have shown that Tregs affect the magnitude of immunity and outcome of viral infections, especially with persistent viruses that give rise to chronic lesions (Rouse BT, 2006). Depletion of Tregs prior to infection using a monoclonal antibody against the IL-2receptor results in enhanced in vivo CD8+ and CD4+ T lymphocyte proliferation, and increased mucosa l antibody levels in response to herpes Tregs play a vital role in preventing what Khatami terms “pathogen-induced immunological chaos,” the “immune tsunami,” or cytokine storm can then lead to inflammatory disease and cancer(Khatami, 2011). Immunologists are currently trying to identify strategies to enhance regulatory T cell activation to protect against inflammatory disease such as systemic lupus erythematosis and rheumatoid arthritis. However, some viruses, including PRRSV in pigs, have exploited these cells to enhance their survival and replication in the host. Activation of regulatory T cells by viruses dampens the immune response to the virus and allows them to replicate and persist in host tissues . Understanding the mechanism of Treg activation by viruses is critical for identifying new strategies to prevent the effects on the host.
http://cdn.intechopen.com/pdfs/31357/InTech-Regulatory_t_cells_and_viral_disease.pdf
Quote
Development of virus-specific CD4+ and CD8+ regulatory T cells induced by human herpesvirus-6 infection Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus. The mechanisms by which HHV-6 establishes latency and immunosuppression in its host are not well understood. Here we characterized HHV-6-specific T cells in peripheral blood mononuclear cells (PBMCs) from HHV-6-infected donors. Our results showed that HHV-6 infection could induce both CD4+ and CD8+ HHV-6-specific regulatory T (Treg) cells. These HHV-6-specific Treg cells had potent suppressive activity and expressed high levels of Treg-associated molecules CD25, FoxP3 and GITR. Both CD4+ and CD8+ Treg cells secreted IFN-γ, IL-10, but little or no IL-2, IL-4 or TGF-β. Furthermore, HHV-6-specifc Treg cells could not only suppress naïve and HHV-6-specific CD4+ effector T cell immune responses, but also impair dendritic cell (DC) maturation and functions. In addition, the suppressive effects mediated by HHV-6-specific Treg cells were mainly through a cell-to-cell contact dependent mechanism, but not through the identified cytokines. These results suggest that HHV-6 may utilize the induction of Treg cells as a strategy to escape anti-virus immune responses and maintain the latency and immunosuppression in infected hosts.
Quote
Human herpesvirus-6-specific interleukin 10-producing CD4+ T cells suppress the CD4+ T-cell response in infected individuals.
Human herpesvirus-6 (HHV-6) infection normally persists for the lifetime of the host and may reactivate with immunosuppression. The mechanism behind HHV-6 latent infection is still not fully understood. In this study, we observed that decreased proliferation of CD4+ T cells and PBMCs but not CD8+ T cells from HHV-6-infected individuals was stimulated with HHV-6-infected cell lysates. Moreover, HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals have suppressive activity on naïve CD4+ T and CD8+ T cells from HHV-6-uninfected individuals. However, no increased proportion of CD4+ CD25+ Treg cells from HHV-6-infected individuals contributed to the suppressive activity of the HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals. Transwell experiments, ELISA and anti-IL-10 antibody blocking experiment demonstrated that IL-10 may be the suppressive cytokine required for suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interleukin (IL)-10 and IL-4 further implicated the HHV-6-specific IL-10-producing CD4+ T cells in the suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interferon (IFN)-gamma demonstrated a decreased frequency of HHV-6-specific IFN-gamma-producing CD4+ T, but not CD8+ T cells in HHV-6-infected individuals, indicating that it was the CD4+ Th1 responses in HHV-6-infected individuals that were selectively impaired. Our findings indicated that HHV-6-specific IL-10-producing CD4+ T cells from HHV-6-infected individuals possess T regulatory type 1 cell activity: immunosuppression, high levels of IL-10 production, with a few cells expressing IFN-gamma, but none expressing IL-4. These cells may play an important role in latent HHV-6 infection.
Quote
In humans, a P. falciparum-mediated (Malaria) conversion of CD4(+)CD25(-) T cells into CD25+Foxp3+CD4+ T cells has been described. Induction of Foxp3 cells in vitro required TGF-β1 and IL-10, and these cells show the typical suppressor phenotype (CTLA-4(+), CD127(low), CD39(+), ICOS(+), TNFRII(+)) [104].
In accordance, an increase in systemic IL-10 and TGF-β that correlates with up-regulation of CD4+CD25+Foxp3+ has been observed in humans infected with P. falciparum and P. vivax [105, 106].
Quote
By selectively altering the numbers of these cells either by targeted depletion with monoclonal antibody or adoptive transfer of highly enriched naïve CD25+ cells prior to infection, we show that
Tregs impairs efficient parasite control and impacts on production of disease-exacerbating proinflammatory cytokines. Collectively, our findings suggest that Tregs contribute to enhanced susceptibility to experimental T. congolense infection in mice.
http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001761
