Maintenance and Polarization of Human TH2 Central Memory T Cells by Thymic Stromal Lymphopoietin-Activated Dendritic Cells

Abstract

The identity of TH2 memory cells and the mechanism regulating their maintenance during allergic inflammation remain elusive. We report that circulated human CD4+ T cells expressing the prostaglandin D2 receptor (CRTH2) are TH2 central memory T cells, characterized by their phenotype, TH2 cytokine production, gene-expression profile, and the ability to respond to allergens. Only dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) can induce a robust expansion of CRTH2+CD4+ TH2 memory cells, while maintaining their central memory phenotype and TH2 commitments. CRTH2+CD4+ TH2 memory cells activated by TSLP-DCs undergo further TH2 polarization and express cystatin A, Charcot-Leydon crystal protein, and prostaglandin D2 synthase, implying their broader roles in allergic inflammation. Infiltrated CRTH2+CD4+ TH2 effector memory T cells in skin lesion of atopic dermatitis were associated with activated DCs, suggesting that TSLP-DCs play important roles not only in TH2 priming, but also in the maintenance and further polarization of TH2 central memory cells in allergic diseases.

Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin–Conditioned Dendritic Cells Induce Regulatory T-Cell Differentiation and Protection of NOD Mice Against Diabetes

“…ϩ T-cells cultured with TSLP-DCs produced significantly high amounts of Th2 cytokines, such as IL-4, and low amounts of IFN-␥, as reported previously (38). Furthermore, these cells produced more TGF-␤ and IL-10 than naïve CD4 ϩ T-cells cultured with iDCs or LPS-DCs (Fig.…”

“…Consistent with our results, TSLP blunted the production of IL-12p70, TNF-␣, IFN-␥, or mRNA encoding IL-12 by human dendritic cells and type 1 IFN family members that induce Th1 differentiation (29,44,45). Recent studies have shown that TSLP-DCs induced the expansion of CD4 ϩ and CD8 ϩ T-cells and the differentiation of naïve CD4 ϩ T-cells toward Th2 cells that produced IL-4, IL-13, and TNF-␣ but not IL-10 and IFN-␥ (38,45). In addition, TSLP-DCs have been reported to prime CD8 ϩ T-cells into IL-5-and IL-13-producing effector cells exhibiting poor cytotoxic activity (46).…”

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

“…Recent studies suggested that TSLP functions upstream of IL-13 in the skin and lung allergic inflammation [12,13]. Given the current findings, TSLP may act both upstream and downstream of IL-13 and contribute to the initiation and maintenance of allergic inflammation; TSLP acting upstream of IL-13 may play an important role in the differentiation of Th2 type cells or in the activation of mast cells to produce IL-13 [1, 2, 4, 21] whereas TSLP acting downstream of IL-13 may play an important role in the regulation of Th2 cell function [25], in the maintenance of memory Th2 cells [26], and in the production of chemokines associated with inflammation [27] (Fig. 3).…”

Advances in Assessing the Severity of Atopic Dermatitis

“…In this complex procedure, many chemokines, (such as CCL1, CCL2, CCL11, CCL13, CCL18, CCL20, CCL21, and CCL26) interact with various immune effector cells through their receptors(D.Y. Leung et al, 2004;Homey et al, 2006). AD is a disease with the participation of whole body immune system, and that the immunologic abnormality is not limited to the skin.…”