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Towards a better understanding of Th2 immune response in allergic diseases

The cytokine TSLP, produced by skin keratinocytes, drives Th2 initiation in the lymph nodes through an orchestrated cascade involving a sequential cooperation of dendritic cells, T cells and basophils (steps 1 to 4), which is mediated by two crucial molecules OX40L and IL-3.

Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade.

Leyva-Castillo JM(1), Hener P, Michea P, Karasuyama H, Chan S, Soumelis V, Li M.

Nat Commun 2013

Nov. 28, 2013

The immune system confers critical protection of the organism against pathogens. However, an aberrant immune response, whether diminished or exacerbated, can lead to serious health problems. Allergic diseases such as atopic dermatitis are mediated by an exaggerated Th2 (type 2 T helper) cell response. A new study from a research group led by Dr. Mei Li, as part of P. Chambon & D. Metzger team at the IGBMC, deciphers the cellular and molecular events of the initiation of Th2 immune response, thus providing novel insights on the mechanisms underlying the onset of allergic diseases. These results are published on 28 November 2013 in the journal Nature Communications.


World Health Organization considers allergy as the fourth most common disease in the world after cancer, cardiovascular diseases and AIDS. The frequency of allergic diseases including atopic dermatitis (AD, also known as eczema), asthma, rhinitis, or food allergies has dramatically increased in industrialized countries in the past years, with nearly 30 % of world population affected. Amongst them AD is very common in children (15-20 % of the population affected) and is frequently associated with asthma. A so-called Th2 immune response, mediated by a particular type of T cells, type 2 T helper cells, is critically implicated in the pathogenesis of allergic diseases.


Initial studies by Dr. Mei Li at IGBMC established the central role of TSLP, an inflammatory cytokine produced by skin, in triggering the AD pathogenesis. During last years, this molecule has emerged as a critical player instructing Th2 immune responses involved in allergies as well as other disease states such as autoimmune diseases and cancer. However, little is known about how TSLP initiates and controls Th2 responses within the tissue microenvironment. A new study led by Dr. Li, CNRS research director, in collaboration with researchers at the Institut Curie and the Tokyo Medical and Dental University Graduate School, delineates the TSLP-driven immune network leading to the initiation of Th2 immune responses, for the first time in the in vivo context.


Thanks to their unique mouse modeling system able to induce TSLP in skin keratinocytes, the researchers succeeded in dissecting TSLP-triggered cellular and molecular events in a living organism. By utilizing integrated genetic tools, molecular biology and immunological approaches, their current work shows that skin TSLP initiates Th2 responses through an orchestrated immune cascade. Firstly, expression of TSLP takes place in skin keratinocytes, and then the signal is relayed by dendritic cells that migrate to the lymph nodes. There occurs a sequential cooperation of dendritic cells, T cells and basophils, finally leading to the generation of Th2 cells. Furthermore, their study reveals that such a cellular network is mediated by a signal axis involving two important molecules OX40L and IL-3.       


This study provides novel insights into the cellular and molecular mechanisms underlying the initiation of Th2 immune responses. “We have made a great step forward towards an integrated understanding of complex immune networks in the in vivo context.” says Dr. Li. “The knowledge we acquire will hopefully offer possibilities to develop new therapeutic or preventive strategies for human allergies, as well as other diseases related to Th2 immunity.”


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