PKCλ/ι regulates Th17 cells and house dust mite-induced allergic airway inflammation

Abstract Asthma is a chronic airway inflammatory disease affecting millions of people in the world. CD4+ T helper cells play central roles in its pathogenesis. We have reported that atypical protein kinase PKCλ/ι regulates Th2 differentiation and function. Recently, we found that PKCλ/ι was involved in the regulation of Th17 differentiation and function. PKCλ/ι-deficient CD4+ T cells showed impaired ability to differentiate into Th17 cells in vitro under Th17-polarizing culture conditions. The secretion of IL-17, IL-17F, IL21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-polarizing and Th17-polarizing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorgt, key Th17 transcription factors. On the other hand, PKCλ/ι did not affect the development and induction of regulatory T (Treg) cells. In order to study the in vivo roles of PKCλ/ι-Th17 axis, we applied a murine model of house dust mites (HDM)-induced allergic airway inflammation, in which Th17 cells and neutrophils are dominant responder among others. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 and Th2 effector cytokines, such as IL-17, IL-4, IL-5 and IL-13 were inhibited in the bronchoalveolar lavage fluids. Their mRNA levels in the lungs were also significantly downregulated. Thus, PKCλ/ι emerges as an important regulator of Th17 differentiation and allergic airway inflammation. Further investigations are underway to explore the underlying molecular mechanisms.