Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4.

Background: IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders. Objective: Study of the relationship between human IL-17A–producing CD4⁺ T_H cells (T_H17) and IL-4–producing CD4⁺ T_H (T_H2) cells. Methods: T-cell clones generated from the CCR6⁺CD161⁺ fraction of human circulating CD4⁺ T cells, which contains virtually all T_H17 cells, as well as circulating CD4⁺ T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile. Results: A small proportion of CCR6⁺CD161⁺CD4⁺ T-cell clones showed the ability to produce both IL-17A and IL-4 (T_H17/T_H2). T_H17/T_H2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few T_H17/T_H2 cells were found among circulating CD4⁺ T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. T_H17/T_H2 cells could not be derived from naive umbilical cord blood CD4⁺ T cells under any experimental condition. However, when circulating memory CCR6⁺CD161⁺CD4⁺ T cells were cloned under appropriate polarizing conditions, T_H17/T_H2 clones originated in the presence of IL-4, suggesting that an IL-4–rich microenvironment may induce the shifting of memory T_H17 cells into T_H17/T_H2 cells. Conclusion: Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of T_H17/T_H2 cells may play some role in the pathogenesis of this disease. [Copyright &y& Elsevier]