Interleukin‐25 initiates Th2 differentiation of human CD4⁺ T cells and influences expression of its own receptor

Abstract

Human CRTh2+ Th2 cells express IL‐25 receptor (IL‐25R) and IL‐25 has been shown to potentiate production of Th2 cytokines. However, regulation of IL‐25R and whether it participates in Th2 differentiation of human cells have not been examined. We sought to characterize IL‐25R expression on CD4+ T cells and determine whether IL‐25 plays a role in Th2 differentiation. Naïve human CD4+ T cells were activated in the presence of IL‐25, IL‐4 (Th2 conditions) or both cytokines to assess their relative influence on Th2 differentiation. For experiments with differentiated Th2 cells, CRTh2‐expressing cells were isolated from differentiating cultures. IL‐25R, GATA3, CRTh2 and Th2 cytokine expression were assessed by flow cytometry, qRT‐PCR and ELISA. Expression of surface IL‐25R was induced early during Th2 differentiation (2 days). Addition of IL‐25 to naïve CD4+ T cells revealed that it induces expression of its own receptor, more strongly than IL‐4. IL‐25 also increased the proportions of IL‐4‐, GATA3‐ and CRTh2‐expressing cells and expression of IL‐5 and IL‐13. Activation of differentiated CRTh2+ Th2 cells through the TCR or by CRTh2 agonist increased surface expression of IL‐25R, though re‐expression of CRTh2 following TCR downregulation was impeded by IL‐25. These data suggest that IL‐25 may play various roles in Th2 mediated immunity. We establish here it regulates expression of its own receptor and can initiate Th2 differentiation, though not as strongly as IL‐4.

Pathogenic CD4 + T cells in patients with asthma

“…65 In addition to amplifying established T H 2 responses, IL-25 acts directly on naive human CD4 + T cells to induce T H 2 differentiation, although not to the same extent as the prototypical T H 2-differentiating cytokine IL-4. 66 IL-25 also mirrors the direct effects of IL-33 on memory T H 2 cells in the context of chronic rhinosinusitis. 62 These actions, coupled with an association between IL-25 and T H 2-high asthma, 67 support a pathogenic role for IL-25 in T H 2-driven airway disease resembling that of IL-33.…”

Blockade of RGMb inhibits allergen-induced airways disease

“…Levels of both IL-25 and IL-17RB mRNA and protein increase in the lungs after infection with respiratory syncytial virus or rhinovirus 35,47 or after allergen exposure, as shown in the present study and in a previous study. 4 IL-25 was shown to induce IL-17RB surface expression by human CD4 1 T cells, 48 and IL-17RB expression by human monocytic cells was induced and amplified by IL-4 and IL-25. 49 We found that although about 50% of the RGMb 1 interstitial macrophages taken directly from inflamed lungs expressed IL-17RB, on incubation with rIL-25, expression increased to greater than 98%.…”

Comparative Efficacy of Glucocorticoid Receptor Agonists on Th2 Cell Function and Attenuation by Progesterone

“…To directly compare the ability of dexamethasone and prednisolone to suppress type 2 cytokine production, primary Th2 cells (Supplemental Figure 1 (Figure S1)) [42,43] cultured in IL-2 (4 days) were treated (24 hours) with equimolar concentrations of either CS (10 -9 -10 -7 M) as in [15,18]. Moreover, these concentrations are within the pharmacological range [44].…”

“…Cytokine expression Intracellular staining to characterize primary Th2 cells was previously described in [42,43]. Brie y, cytokine staining for IL-4, IL-13 and IFNγ was performed following 4 hours of stimulation with PMA (20ng/mL) and ionomycin (1 μM) in the presence of Brefeldin A (10 μg/mL, all from Sigma Aldrich, Canada).…”