Abstract
Interleukin-10 (IL-10) is an important regulatory cytokine required to control allergy and asthma. IL-10-mediated regulation of T cell-mediated responses was previously thought to occur indirectly via antigen-presenting cells. However, IL-10 can act directly on regulatory T cells and T helper type 17 (Th17) cells. In the context of allergy, it is therefore unclear whether IL-10 can directly regulate T helper type 2 (Th2) cells and whether this is an important regulatory axis during allergic responses. We sought to determine whether IL-10 signaling in CD4+ Th2 cells was an important mechanism of immune regulation during airway allergy. We demonstrate that IL-10 directly limits Th2 cell differentiation and survival in vitro and in vivo. Ablation of IL-10 signaling in Th2 cells led to enhanced Th2 cell survival and exacerbated pulmonary inflammation in a murine model of house dust mite allergy. Mechanistically, IL-10R signaling regulated the expression of several genes in Th2 cells, including granzyme B. Indeed, IL-10 increased granzyme B expression in Th2 cells and led to increased Th2 cell death, identifying an IL-10-regulated granzyme B axis in Th2 cells controlling Th2 cell survival. This study provides clear evidence that IL-10 exerts direct effects on Th2 cells, regulating the survival of Th2 cells and severity of Th2-mediated allergic airway inflammation.
Highlights
Interleukin-10 (IL-10) is a potent regulator of inflammatory responses[1] and plays a critical role in controlling allergic airway inflammation.[2]
IL-10R signaling in T cells regulates Th2 cell differentiation and house dust mite (HDM)-induced airway allergy
To investigate whether IL-10 signaling in T cells was important during airway allergy, we conditionally deleted the IL-10 receptor-a (IL-10RA) subunit in T cells by crossing Il10rafl/fl mice with Cd4Cre mice.[19]
Summary
Interleukin-10 (IL-10) is a potent regulator of inflammatory responses[1] and plays a critical role in controlling allergic airway inflammation.[2] Compared with nonasthmatics, asthmatic individuals have been reported to have reduced levels of IL10 in bronchoalveolar lavage fluid,[3] with decreased secretion of IL-10 from alveolar macrophages.[4] polymorphisms in the IL10 gene resulting in low IL-10 production have been associated with severe asthma,[5] suggesting that IL-10 is a major determinant in the development and severity of airway allergy. Il10–/– mice develop enhanced allergic responses to a variety of allergens[6,7,8] and develop increased eosinophilic airway inflammation. These studies highlight a clear non-redundant role for IL-10 in controlling allergen-induced airway disease. The precise mechanisms are unclear, successful allergen-specific immunotherapy correlates with the development of IL-10-secreting antigen-specific T cells,[10] suggesting that the balance between IL10-secreting cells and pathogenic cells is an important determinant in the development of allergic disease.[11]
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