Ex vivo activated OVA specific and non-specific CD4+CD25+ regulatory T cells exhibit comparable suppression to OVA mediated T cell responses

Naturally occurring Foxp3+CD4+CD25+ T cells isolated from lungs of naive mice regulate lung allergic airway hyperresponsiveness, inflammation, levels of Th2 cytokines, and mucus production. OVA-specific (αβTCR+) CD4+CD25+ T cells suppressed ragweed-induced airway hyperresponsiveness and inflammation as did anti-TCR-treated OVA-specific CD4+CD25+ T cells, suggesting that Ag-specificity was not required for expression of regulatory activities. Suppression was associated with increased levels of IL-10 and TGF-β; decreased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid; and reduced recruitment and activation of CD8+ T cells in the airways. Following intratracheal administration, OVA-specific CD4+CD25+ T cells were identified in both the airway lumens and lung parenchyma, and in some instances in close proximity to host CD8+ T cells. These results demonstrate that the regulatory activities of naturally occurring Foxp3+CD4+CD25+ T cells on lung allergic responses are Ag-nonspecific and thus, independent of Ag-specific recognition.

contrasting

confidence: 66%

“…Similarly, Ag-specific and nonspecific nTregs were equally effective in preventing delayed type hypersensitivity (26) and once activated via the TCRs in vitro, the suppressive function of CD4 ϩ CD25 ϩ from transgenic donors was shown to be Ag-nonspecific (22).…”

Section: Cd4mentioning

confidence: 99%

Antigen Specificity Is not Required for Modulation of Lung Allergic Responses by Naturally Occurring Regulatory T Cells

Joetham

Takeda

Okamoto

et al. 2009

“…It has been reported that Treg cells inhibits T cell response against allergic Ags and production of Th2 cytokines (43)(44)(45)(46). Because silencing of CD40 was also associated with acquisition of a tolerogenic or Treg-generating DC subset, we sought to determine whether allergic responses might benefit from such an approach.…”

Section: Discussionmentioning

confidence: 99%

Novel Vaccination for Allergy through Gene Silencing of CD40 Using Small Interfering RNA

Suzuki

Zheng

Zhang

et al. 2008

Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silencing strategies using siRNA have demonstrated therapeutic benefits in animal models of various diseases, and are currently in clinical trials. However, the utility of gene silencing as a treatment for allergic diseases has not yet been reported. In this study, we report a novel therapy for allergy through gene silencing of CD40, a critical costimulatory molecule and a key factor in allergic immune responses. Silencing CD40 resulted in generation of immunoregulatory dendritic cells (DCs). Administration of CD40 siRNA remarkably reduced nasal allergic symptoms and local eosinophil accumulation in the OVA-induced allergic mice. The OVA-specific T cell response was inhibited after the CD40 siRNA treatment. Additionally, anti-OVA specific IgE and production of IL-4 and IL-5 of T cells stimulated by OVA were significantly decreased in CD40 siRNA-treated mice. Furthermore, we demonstrated that the therapeutic effects by CD40 siRNA were associated with impaired Ag-presenting functions of DCs and B cells, and generation of regulatory T cells. The present study highlights a therapeutic potential of siRNA-based treatment for allergic diseases.

“…Th1 cells were generated and adoptively transferred as previously described (36) with the following modifications. CD4+CD25- T cells from BALB/c: +/+: DO11.10 mice (1× 10 6 cells/ml) were cultured with T-cell depleted irradiated splenocytes (2 × 10 6 cells/ml), 1μg/ml of OVA peptide, 10μg/ml of anti-mouse IL-4 neutralization antibody (R&D systems, Minneapolis, MN) and 10ng/ml of recombinant mIL-12 (R&D systems, Minneapolis, MN) in 24-well plates.…”

Section: Methodsmentioning

confidence: 99%

The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

Iype

Sankarshanan

Mauldin

et al. 2010

The importance of regulatory T cells (Tregs) for immune tolerance is well recognized, yet the signaling molecules influencing their suppressive activity are relatively poorly understood. In this article, through in vivo studies and complementary ex vivo studies, we make several important observations. First, we identify the cytoplasmic tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) as an endogenous brake and modifier of the suppressive ability of Tregs; consistent with this notion, loss of SHP-1 expression strongly augments the ability of Tregs to suppress inflammation in a mouse model. Second, specific pharmacological inhibition of SHP-1 enzymatic activity via the cancer drug sodium stibogluconate potently augmented Treg suppressor activity both in vivo and ex vivo. Finally, through a quantitative imaging approach, we directly demonstrate that Tregs prevent the activation of conventional T cells and that SHP-1–deficient Tregs are more efficient suppressors. Collectively, our data reveal SHP-1 as a critical modifier of Treg function and a potential therapeutic target for augmenting Treg-mediated suppression in certain disease states.