Interleukin-31 (IL-31) is a recently-discovered Th2-cell-derived cytokine which can induce severe pruritus and skin lesions such as atopic dermatitis (AD). IL-31 mRNA and protein expressions are largely restricted to CD4+ T cells, particularly CD45RO+ (memory) CLA+ T cells. However, the mechanism of IL-31 production in these cells is not fully recognized yet. 
Histamine-4-receptor (H4R) is a recently described type of histamine receptor upregulated under Th2 conditions, and HR4 stimulation leads to the induction of IL-31 in vitro. However, the mechanism and association between IL-31 and H4R in human has not been reported. The purpose of the present study is to evaluate the hypothesis that H4R+ CLA+ CD45RO+ T cells produce IL-31 predominantly. 
To investigate that H4R+ cells produced IL-31, immunofluorescence studies were performed on punch biopsy specimens of 5 AD, 3 prurigo nodularis and 3 healthy controls. In addition, blood samples were collected from 12 AD patients and healthy controls. The H4R+ CLA+ CD45RO+ T cells and the other cells were sorted by fluorescence-activated cell sorting (FACS). These sorted cells were stimulated with 4-methylhistamine and the level of IL-31 in the culture supernatant were measured by enzyme-linked immunosorbent assay.
Under high-power field, the IL-31+ H4R+ colocalized cell counts 12.9 ± 9.2, 6.7 ± 6.0 and 0.0 ± 0.0 in AD, prurigo nodularis, and control samples, respectively (p<0.01). The result of FACS showed that the proportion of H4R+ CLA+ CD45RO+ T cells were 31.5 ± 9.6% and 23.1 ± 5.2% in AD and healthy control, respectively. These cells showed increased production of IL-31 in both stable and stimulated status (p<0.05).
According to our study, H4R+ CLA+ CD45RO+ T cells are a major source of IL-31, and this subset may be targets for the treatment of IL-31 induced pruritus.

Interleukin 31 production is associated with Histamine H4 receptor of CLA+ CD45RO+ T cell