Role of CD4⁺CD25⁺Regulatory T Cells in T Helper 2 Cell-mediated Allergic Inflammation in the Airways

Abstract

It has recently been shown that CD4(+) CD25(+) T cells are immunoregulatory T cells that prevent CD4(+) T cell-mediated organ-specific autoimmune diseases. To determine whether CD4(+) CD25(+) T cells downregulate Th2 cell-mediated allergic inflammation in the airways, we studied antigen-induced eosinophil recruitment in the airways in BALB/c Rag-2(-)(/-) mice transferred with CD4(+) CD25(+) T cell-depleted or unfractionated T cells from ovalbumin-specific TCR transgenic mice. Antigen-induced eosinophil recruitment into the airways was significantly decreased in the mice transferred with CD4(+) CD25(+) T cell-depleted splenocytes as compared with those transferred with unfractionated splenocytes. On the other hand, the depletion of CD4(+) CD25(+) T cells increased antigen-induced neutrophil and T cell recruitment in the airways of the mice. The depletion of CD4(+) CD25(+) T cells also decreased antigen-induced IL-4 and IL-5 production in the airways of the mice. Finally, the depletion of CD4(+) CD25(+) T cells prevented antigen-induced Th2 cell differentiation in vitro but increased the differentiation of Th1 cells. These results indicate that CD4(+) CD25(+) T cells modulate the Th1 and Th2 cell balance toward Th2 cells and thus upregulate Th2 cell-mediated allergic inflammation in the airways.

CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

“…Conceivably, CD4 ؉ CD25 ؉ T cells may influence either the maturation of Th2 cells directly or act by inhibiting Th1 development (i.e., cross-regulation). Using the DO11.10 model of airway inflammation, it has been suggested that regulatory T cells favor Th2 polarization by inhibiting Th1 development (35). However, in our experiments, the Th2 cells prepared from CD4 ϩ CD25 Ϫ T cells did not produce any detectable IFN-␥, even after adoptive transfer into mice that were then repeatedly exposed to OVA aerosols.…”

Targeting of CD25 and Glucocorticoid-Induced TNF Receptor Family-Related Gene-Expressing T Cells Differentially Modulates Asthma Risk in Offspring of Asthmatic and Normal Mother Mice

“…This indicates that Treg not only suppress Th1 responses (61) but are also critical to control Th2 cytokine production in normal conditions (13). Conversely, the fact that PC61 pretreatment led to decreased IL-4 and IL-13 production in offspring born of asthmatic mothers indicates that Treg, in pathological conditions, can promote local Th2 cytokine imbalance in newborn as previously observed in adult mice (62).…”

Activation of naturally occurring lung CD4+CD25+regulatory T cells requires CD8 and MHC I interaction

“…Their suppressive activity both in vitro and in vivo appears to be mediated by several mechanisms depending on the model used and includes cell-to-cell contact (27,36,37) and the release of IL-10 (9, 38) and 39,40). A possible mechanism of suppression in humans is the cytolytic activity of CD4 ϩ CD25 ϩ regulatory T cells that are granzyme-and perforin-mediated (41).Although the regulatory profiles of CD4 ϩ CD25 ϩ T cells have been described in mouse models of allergen-induced AHR and airway inflammation (9,34,35), the mechanisms that direct the functional activation of these regulatory activities have not been well defined. In the present study, we investigated the role of MHC I on naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (nTregs) and the requirement for interaction with CD8 in the lung and show that interactions between MHC I and CD8 are essential for the expression of the immunoregulatory properties of nTregs on lung allergic responses.…”

“…Although the regulatory profiles of CD4 ϩ CD25 ϩ T cells have been described in mouse models of allergen-induced AHR and airway inflammation (9,34,35), the mechanisms that direct the functional activation of these regulatory activities have not been well defined. In the present study, we investigated the role of MHC I on naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (nTregs) and the requirement for interaction with CD8 in the lung and show that interactions between MHC I and CD8 are essential for the expression of the immunoregulatory properties of nTregs on lung allergic responses.…”

“…They are anergic (27,28) and express CTLA-4 (CD152) (29), glucocorticoid-induced TNF receptor (30), and the transcription factor Foxp3, which appears to be specific for CD4 ϩ CD25 ϩ regulatory T cells (25,26). They have been shown to suppress allergen-driven T cell activation (9,31,32) and regulate Th2 immune responses in humans (33) and animals (34,35) and modulate both T cell activation and Th2 cytokine skewing (9). Their suppressive activity both in vitro and in vivo appears to be mediated by several mechanisms depending on the model used and includes cell-to-cell contact (27,36,37) and the release of IL-10 (9, 38) and TGF-␤ (9,39,40).…”